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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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New drug discovery: Where are we heading to?


 

To start with the simplest one is Quantitative structure-activity relationship (QSAR) which is also referred to as 2D-QSAR sometimes. 3D-QSAR involving Comparative Molecular Field Analysis (CoMFA) and Comparative molecular similarity index analysis (CoMSIA) are extension of QSAR. QSAR is not able to take the three dimensional structure of a molecule into consideration due to absence of three-dimensional parameterization of structures. 3D-QSAR scores over QSAR in this respect. Docking studies throw more light on the binding modes of drugs with their target proteins but it is feasible only when the crystal structure of the target enzyme/protein is known with good resolution. Docking studies are also used for virtual screening of databases. But the ideal technique for virtual screening of compounds is through pharmacophore mapping and screening, especially when the structure of the target is not known. Very large databases can be first screened by pharmacophorebecause the technique is quite fast followed by screening of the positive hits using docking studies. Insilico designing of novel compounds can also be performed using deNovodesigning techniques subject to the condition that the target structure in known.

Yadav M R. New drug discovery: Where are we heading to?. J Adv Pharm Technol Res 2013;4:2-3

 

URL:
Yadav M R. New drug discovery: Where are we heading to?. J Adv Pharm Technol Res [serial online] 2013 [cited 2014 Aug 12];4:2-3. Available from: http://www.japtr.org/text.asp?2013/4/1/2/107493

 

http://www.japtr.org/article.asp?issn=2231-4040;year=2013;volume=4;issue=1;spage=2;epage=3;aulast=Yadav

Design, construction and start-up of a pilot plant for active pharmaceutical ingredients


Linde-KCA-Dresden built a pilot plant 16 times the size of the laboratory apparatus for Novo Nordisk A/S
Linde-KCA-Dresden built a pilot plant 16 times the size of the laboratory apparatus for Novo Nordisk A/S
The building layouts show different areas for the pilot plant, the utility systems and the technical rooms with hazardous and non-hazardous proof conditions (top). The engineering documents include the piping and instrumentation diagrams, the manufacturer vessel drawings as well as the 3D model with the isometric drawings of the pipes (bottom)
The building layouts show different areas for the pilot plant, the utility systems and the technical rooms with hazardous and non-hazardous proof conditions (top). The engineering documents include

The construction of a pilot plant constitutes an important milestone in the development cycle of a new active pharmaceutical ingredient. Pilot plants are used to gain the technological experience needed for the scale-up process and are required for producing sufficient quantities of the active pharmaceutical ingredient for clinical trials and other types of tests. As a result, even these testing facilities must comply with GMP regulations.

http://www.cpp-net.com/pharma/-/article/5829537/15910929/Challenging+task/

The FDA’s Drug Review Process: Ensuring Drugs Are Safe and Effective


How Drugs are Developed and Approved

The mission of FDA’s Center for Drug Evaluation and Research (CDER) is to ensure that drugs marketed in this country are safe and effective. CDER does not test drugs, although the Center’s Office of Testing and Research does conduct limited research in the areas of drug quality, safety, and effectiveness.

CDER is the largest of FDA’s five centers.   It has responsibility for both prescription and nonprescription or over-the-counter (OTC) drugs. For more information on CDER activities, including performance of drug reviews,  post-marketing risk assessment, and other highlights, please see the CDER Update: Improving Public Health Through Human Drugs The other four FDA centers have responsibility for medical and radiological devices, food, and cosmetics, biologics, and veterinary drugs.

Some companies submit a new drug application (NDA) to introduce a new drug product into the U.S. Market.  It is the responsibility of the company seeking to market a drug to test it and submit evidence that it is safe and effective. A team of CDER physicians, statisticians, chemists, pharmacologists, and other scientists reviews the sponsor’s NDA containing the data and proposed labeling.

The section below entitled From Fish to Pharmacies: The Story of a Drug’s Development, illustrates how a drug sponsor can work with FDA’s regulations and guidance information to bring a new drug to market under the NDA process.

From Fish to Pharmacies:  A Story of Drug Development

Osteoporosis, a crippling disease marked by a wasting away of bone mass, affects as many as 2 million American, 80 percent of them women, at an expense of $13.8 billion a year, according to the National Osteoporosis Foundation.,  The disease may be responsible for 5 million fractures of the hip, wrist and spine in people over 50, the foundation says, and may cause 50,000 deaths. Given the pervasiveness of osteoporosis and its cost to society, experts say it is crucial to have therapy alternatives if, for example, a patient can’t tolerate estrogen, the first-line treatment.

Enter the salmon, which, like humans, produces a hormone called calcitonin that helps regulate calcium and decreases bone loss.  For osteoporosis patients, taking salmon calcitonin, which is 30 times more potent than that secreted by the human thyroid gland, inhibits the activity of specialized bone cells called osteoclasts that absorb bone tissue.  This enables bone to retain more bone mass.

Though the calcitonin in drugs is based chemically on salmon calcitonin, it is now made synthetically in the lab in a form that copies the molecular structure of the fish gland extract.  Synthetic calcitonin offers a simpler, more economical way to create large quantities of the product.

FDA approved the first drug based on salmon calcitonin in an injectable. Since then, two more drugs, one injectable and one administered through a nasal spray were approved.  An oral version of salmon calcitonin is in clinical trials now.  Salmon calcitonin is approved only for postmenopausal women who cannot tolerate estrogen, or for whom estrogen is not an option.

How did the developers of injectable salmon calcitonin journey “from fish to pharmacies?”

After obtaining promising data from laboratory studies, the salmon calcitonin drug developers took the next step and submitted an Investigational New Drug (IND) application to CDER.  The IND Web page explains the need for this application, the kind of information the application should include, and the Federal regulations to follow.

Once the IND application is in effect, the drug sponsor of salmon calcitonin could begin their clinical trials.  After a sponsor submits an IND application, it must wait 30 days before starting a clinical trial to allow FDA time to review the prospective study.  If FDA finds a problem, it can order a  “clinical hold” to delay an investigation, or interrupt a clinical trial if problems occur during the study.

Clinical trials are experiments that use human subjects to see whether a drug is effective, and what side effects it may cause.  The Running Clinical Trials Webpage provides links to the regulations and guidelines that the clinical investigators of salmon calcitonin must have used to conduct a successful study, and to protect their human subjects.

The salmon calcitonin drug sponsor analyzed the clinical trials data and concluded that enough evidence existed on the drug’s safety and effectiveness to meet FDA’s requirements for marketing approval.  The sponsor submitted a New Drug Application (NDA) with full information on manufacturing specifications, stability and bioavailablility data, method of analysis of each of the dosage forms the sponsor intends to market, packaging and labeling for both physician and consumer, and the results of any additional toxicological studies not already submitted in the Investigational New Drug application.  The NDA Web page   provides resources and guidance on preparing the NDA application, and what to expect during the review process.

New drugs, like other new products, are frequently under patent protection during development. The patent protects the salmon calcitonin sponsor’s investment in the drug’s development by giving them the sole right to sell the drug while the patent is in effect.   When the patents or other periods of exclusivity on brand-name drugs expire, manufacturers can apply to the FDA to sell generic versions. TheAbbreviated New Drug Applications (ANDA) for Generic Drug Products Webpageprovides  links to guidances, laws, regulations, policies and procedures, plus other resources to assist in preparing and submitting applications.

Bringing Nonprescription Drug Products to the Market Under an OTC Monograph

OTC drugs can be brought to the market following the NDA process as described above or under an OTC monograph. Each OTC drug monograph is a kind of “recipe book” covering acceptable ingredients, doses, formulations, labeling, and, in some cases, testing parameters. OTC drug monographs are continually updated to add additional ingredients and labeling as needed. Products conforming to a monograph may be marketed without FDA pre-approval. The NDA and monograph processes can be used to introduce new ingredients into the OTC marketplace. For example, OTC drug products previously available only by prescription are first approved through the NDA process and their “switch” to OTC status is approved via the NDA process. OTC ingredients marketed overseas can be introduced into the U.S. market via a monograph under a Time and Extent Application (TEA) as described in 21 CFR 330.14. For a more thorough discussion of how OTC drug products are regulated visit  FDA laws, regulations and guidances that affect small business. Information is also provided on financial assistance and incentives that are available for drug development.

CDER Small Business and Industry Assistance (CDER SBIA)

Drug sponsors which qualify as small businesses can take advantage of special offices and programs designed to help meet their unique needs. The CDER Small Business and Industry Assistance (CDER SBIA) Webpage provides links to FDA laws, regulations and guidances that affect small business. Information is also provided on financial assistance and incentives that are available for drug development.

 

The path a drug travels from a lab to your medicine cabinet is usually long, and every drug takes a unique route. Often, a drug is developed to treat a specific disease. An important use of a drug may also be discovered by accident.

For example, Retrovir (zidovudine, also known as AZT) was first studied as an anti-cancer drug in the 1960s with disappointing results. Twenty years later, researchers discovered the drug could treat AIDS, and Food and Drug Administration approved the drug, manufactured by GlaxoSmithKline, for that purpose in 1987.

Most drugs that undergo preclinical (animal) testing never even make it to human testing and review by the FDA. The drugs that do must undergo the agency’s rigorous evaluation process, which scrutinizes everything about the drug–from the design of clinical trials to the severity of side effects to the conditions under which the drug is manufactured.

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Stages of Drug Development and Review Banner

Animal Testing Icon

Investigational New Drug Application (IND)–The pharmaceutical industry sometimes seeks advice from the FDA prior to submission of an IND.

Sponsors–companies, research institutions, and other organizations that take responsibility for developing a drug. They must show the FDA results of preclinical testing in laboratory animals and what they propose to do for human testing. At this stage, the FDA decides whether it is reasonably safe for the company to move forward with testing the drug in humans.

IND Application Icon

Clinical Trials–Drug studies in humans can begin only after an IND is reviewed by the FDA and a local institutional review board (IRB). The board is a panel of scientists and non-scientists in hospitals and research institutions that oversees clinical research.

IRBs approve the clinical trial protocols, which describe the type of people who may participate in the clinical trial, the schedule of tests and procedures, the medications and dosages to be studied, the length of the study, the study’s objectives, and other details. IRBs make sure the study is acceptable, that participants have given consent and are fully informed of their risks, and that researchers take appropriate steps to protect patients from harm.

Phase 1 Clinical Trial Icon

Phase 1 studies are usually conducted in healthy volunteers. The goal here is to determine what the drug’s most frequent side effects are and, often, how the drug is metabolized and excreted. The number of subjects typically ranges from 20 to 80.

Phase 2 Clinical Trial Icon
Phase 2 studies begin if Phase 1 studies don’t reveal unacceptable toxicity. While the emphasis in Phase 1 is on safety, the emphasis in Phase 2 is on effectiveness. This phase aims to obtain preliminary data on whether the drug works in people who have a certain disease or condition. For controlled trials, patients receiving the drug are compared with similar patients receiving a different treatment–usually an inactive substance (placebo), or a different drug. Safety continues to be evaluated, and short-term side effects are studied. Typically, the number of subjects in Phase 2 studies ranges from a few dozen to about 300.

Phase 3 Clinical Trial Icon

At the end of Phase 2, the FDA and sponsors try to come to an agreement on how large-scale studies in Phase 3 should be done. How often the FDA meets with a sponsor varies, but this is one of two most common meeting points prior to submission of a new drug application. The other most common time is pre-NDA–right before a new drug application is submitted.
Phase 3 studies begin if evidence of effectiveness is shown in Phase 2. These studies gather more information about safety and effectiveness, studying different populations and different dosages and using the drug in combination with other drugs. The number of subjects usually ranges from several hundred to about 3,000 people.

Review Meeting Icon

Postmarket requirement and commitment studies are required of or agreed to by a sponsor, and are conducted after the FDA has approved a product for marketing. The FDA uses postmarket requirement and commitment studies to gather additional information about a product’s safety, efficacy, or optimal use.

NDA Application Icon

New Drug Application (NDA)–This is the formal step a drug sponsor takes to ask that the FDA consider approving a new drug for marketing in the United States. An NDA includes all animal and human data and analyses of the data, as well as information about how the drug behaves in the body and how it is manufactured
Application Reviewed Icon
When an NDA comes in, the FDA has 60 days to decide whether to file it so that it can be reviewed. The FDA can refuse to file an application that is incomplete. For example, some required studies may be missing. In accordance with the Prescription Drug User Fee Act (PDUFA), the FDA’s Center for Drug Evaluation and Research (CDER) expects to review and act on at least 90 percent of NDAs for standard drugs no later than 10 months after the applications are received. The review goal is six months for priority drugs. (See “The Role of User Fees.”)

“It’s the clinical trials that take so long–usually several years,” says Sandra Kweder, M.D., deputy director of the Office of New Drugs in the CDER. “The emphasis on speed for FDA mostly relates to review time and timelines of being able to meet with sponsors during a drug’s development,” she says.

Drug Approval Process Infographic

View larger image and printable PDF version of Drug Approval Process Infographic


Drug Review Steps Simplified

  1. Preclinical (animal) testing.
  2. An investigational new drug application (IND) outlines what the sponsor of a new drug proposes for human testing in clinical trials.
  3. Phase 1 studies (typically involve 20 to 80 people).
  4. Phase 2 studies (typically involve a few dozen to about 300 people).
  5. Phase 3 studies (typically involve several hundred to about 3,000 people).
  6. The pre-NDA period, just before a new drug application (NDA) is submitted. A common time for the FDA and drug sponsors to meet.
  7. Submission of an NDA is the formal step asking the FDA to consider a drug for marketing approval.
  8. After an NDA is received, the FDA has 60 days to decide whether to file it so it can be reviewed.
  9. If the FDA files the NDA, an FDA review team is assigned to evaluate the sponsor’s research on the drug’s safety and effectiveness.
  10. The FDA reviews information that goes on a drug’s professional labeling (information on how to use the drug).
  11. The FDA inspects the facilities where the drug will be manufactured as part of the approval process.
  12. FDA reviewers will approve the application or issue a complete response letter.

Supplemental Information About the Drug Approval Process

Reviewing Applications

Though FDA reviewers are involved with a drug’s development throughout the IND stage, the official review time is the length of time it takes to review a new drug application and issue an action letter, an official statement informing a drug sponsor of the agency’s decision.

Once a new drug application is filed, an FDA review team–medical doctors, chemists, statisticians, microbiologists, pharmacologists, and other experts–evaluates whether the studies the sponsor submitted show that the drug is safe and effective for its proposed use. No drug is absolutely safe; all drugs have side effects. “Safe” in this sense means that the benefits of the drug appear to outweigh the known risks.

The review team analyzes study results and looks for possible issues with the application, such as weaknesses of the study design or analyses. Reviewers determine whether they agree with the sponsor’s results and conclusions, or whether they need any additional information to make a decision.

Each reviewer prepares a written evaluation containing conclusions and recommendations about the application. These evaluations are then considered by team leaders, division directors, and office directors, depending on the type of application.

Reviewers receive training that fosters consistency in drug reviews, and good review practices remain a high priority for the agency.

Sometimes, the FDA calls on advisory committees, who provide FDA with independent opinions and recommendations from outside experts on applications to market new drugs, and on FDA policies.  Whether an advisory committee is needed depends on many things.

“Some considerations would be if it’s a drug that has significant questions, if it’s the first in its class, or the first for a given indication,” says Mark Goldberger, M.D., a former director of one of CDER’s drug review offices. “Generally, FDA takes the advice of advisory committees, but not always,” he says. “Their role is just that–to advise.”Accelerated Approval

Traditional approval requires that clinical benefit be shown before approval can be granted. Accelerated approval is given to some new drugs for serious and life-threatening illnesses that lack satisfactory treatments. This allows an NDA to be approved before measures of effectiveness that would usually be required for approval are available.

Instead, less traditional measures called surrogate endpoints are used to evaluate effectiveness. These are laboratory findings or signs that may not be a direct measurement of how a patient feels, functions, or survives, but are considered likely to predict benefit. For example, a surrogate endpoint could be the lowering of HIV blood levels for short periods of time with anti-retroviral drugs.

Gleevec (imatinib mesylate), an oral treatment for patients with a life-threatening form of cancer called chronic myeloid leukemia (CML), received accelerated approval. The drug was also approved under the FDA’s orphan drug program, which gives financial incentives to sponsors for manufacturing drugs that treat rare diseases. Gleevec blocks enzymes that play a role in cancer growth. The approval was based on results of three large Phase 2 studies, which showed the drug could substantially reduce the level of cancerous cells in the bone marrow and blood.

Most drugs to treat HIV have been approved under accelerated approval provisions, with the company required to continue its studies after the drug is on the market to confirm that its effects on virus levels are maintained and that it ultimately benefits the patient. Under accelerated approval rules, if studies don’t confirm the initial results, the FDA can withdraw the approval.

Because premarket review can’t catch all potential problems with a drug, the FDA continues to track approved drugs for adverse events through a postmarketing surveillance program.

Bumps in the Road

If the FDA decides that the benefits of a drug outweigh the known risks, the drug will receive approval and can be marketed in the United States. But if there are problems with an NDA or if more information is necessary to make that determination, the FDA may issue a complete response letter.

Common problems include unexpected safety issues that crop up or failure to demonstrate a drug’s effectiveness. A sponsor may need to conduct additional studies–perhaps studies of more people, different types of people, or for a longer period of time.

Manufacturing issues are also among the reasons that approval may be delayed or denied. Drugs must be manufactured in accordance with standards called good manufacturing practices, and the FDA inspects manufacturing facilities before a drug can be approved. If a facility isn’t ready for inspection, approval can be delayed. Any manufacturing deficiencies found need to be corrected before approval.

“Sometimes a company may make a certain amount of a drug for clinical trials. Then when they go to scale up, they may lose a supplier or end up with quality control issues that result in a product of different chemistry,” says Kweder. “Sponsors have to show us that the product that’s going to be marketed is the same product that they tested.”

John Jenkins, M.D., director of CDER’s Office of New Drugs, says, “It’s often a combination of problems that prevent approval.” Close communication with the FDA early on in a drug’s development reduces the chance that an application will have to go through more than one cycle of review, he says. “But it’s no guarantee.”

The FDA outlines the justification for its decision in a complete response letter to the drug sponsor and CDER gives the sponsor a chance to meet with agency officials to discuss the deficiencies. At that point, the sponsor can ask for a hearing, correct any deficiencies and submit new information, or withdraw the application.

The Role of User Fees

Since PDUFA was passed in 1992, more than 1,000 drugs and biologics have come to the market, including new medicines to treat cancer, AIDS, cardiovascular disease, and life-threatening infections. PDUFA has allowed the Food and Drug Administration to bring access to new drugs as fast or faster than anywhere in the world, while maintaining the same thorough review process.

Under PDUFA, drug companies agree to pay fees that boost FDA resources, and the FDA agrees to time goals for its review of new drug applications. Along with supporting increased staff, drug user fees help the FDA upgrade resources in information technology. The agency has moved toward an electronic submission and review environment, now accepting more electronic applications and archiving review documents electronically.

The goals set by PDUFA apply to the review of original new human drug and biological applications, resubmissions of original applications, and supplements to approved applications. The second phase of PDUFA, known as PDUFA II, was reauthorized in 1997 and extended the user fee program through September 2002. PDUFA III, which extended to Sept. 30, 2007, was reauthorized in June 2002.

PDUFA III allowed the FDA to spend some user fees to increase surveillance of the safety of medicines during their first two years on the market, or three years for potentially dangerous medications. It is during this initial period, when new medicines enter into wide use, that the agency is best able to identify and counter adverse side effects that did not appear during the clinical trials.

On September 27, 2007, President Bush signed into law the Food and Drug Administration Amendments Act of 2007 which includes the reauthorization and expansion of the Prescription Drug User Fee Act. The reauthorization of PDUFA will significantly broaden and upgrade the agency’s drug safety program, and facilitate more efficient development of safe and effective new medications for the American public.

In addition to setting time frames for review of applications, PDUFA sets goals to improve communication and sets goals for specific kinds of meetings between the FDA and drug sponsors. It also outlines how fast the FDA must respond to requests from sponsors. Throughout a drug’s development, the FDA advises sponsors on how to study certain classes of drugs, how to submit data, what kind of data are needed, and how clinical trials should be designed.

The Quality of Clinical Data

The Food and Drug Administration relies on data that sponsors submit to decide whether a drug should be approved. To protect the rights and welfare of people in clinical trials, and to verify the quality and integrity of data submitted, the FDA’s Division of Scientific Investigations (DSI) conducts inspections of clinical investigators’ study sites. DSI also reviews the records of institutional review boards to be sure they are fulfilling their role in patient protection.

“FDA investigators compare information that clinical investigators provided to sponsors on case report forms with information in source documents such as medical records and lab results,” says Carolyn Hommel, a consumer safety officer in DSI.

DSI seeks to determine such things as whether the study was conducted according to the investigational plan, whether all adverse events were recorded, and whether the subjects met the inclusion/exclusion criteria outlined in the study protocol.

At the conclusion of each inspection, FDA investigators prepare a report summarizing any deficiencies. In cases where they observe numerous or serious deviations, such as falsification of data, DSI classifies the inspection as “official action indicated” and sends a warning letter or Notice of Initiation of Disqualification Proceedings and Opportunity to Explain (NIDPOE) to the clinical investigator, specifying the deviations that were found.

The NIDPOE begins an administrative process to determine whether the clinical investigator should remain eligible to receive investigational products and conduct clinical studies.

CDER conducts about 300-400 clinical investigator inspections annually. About 3 percent are classified in this “official action indicated” category.

The FDA has established an independent Drug Safety Oversight Board (DSOB) to oversee the management of drug safety issues. The Board meets monthly and has representatives from three FDA Centers and five other federal government agencies. The board’s responsibilities include conducting timely and comprehensive evaluations of emerging drug safety issues, and ensuring that experts–both inside and outside of the FDA–give their perspectives to the agency. The first meeting of the DSOB was held in June 2005.

Once the review is complete, the NDA might be approved or rejected. If the drug is not approved, the applicant is given the reasons why and what information could be provided to make the application acceptable. Sometimes the FDA makes a tentative approval recommendation, requesting that a minor deficiency or labeling issue be corrected before final approval. Once a drug is approved, it can be marketed.

Some approvals contain conditions that must be met after initial marketing, such as conducting additional clinical studies. For example, the FDA might request a postmarketing, or phase 4, study to examine the risks and benefits of the new drug in a different population or to conduct special monitoring in a high-risk population. Alternatively, a phase 4 study might be initiated by the sponsor to assess such issues as the longer term effects of drug exposure, to optimize the dose for marketing, to evaluate the effects in pediatric patients, or to examine the effectiveness of the drug for additional indications. Postmarketing surveillance is important, because even the most well-designed phase 3 studies might not uncover every problem that could become apparent once a product is widely used. Furthermore, the new product might be more widely used by groups that might not have been well studied in the clinical trials, such as elderly patients. A crucial element in this process is that physicians report any untoward complications. The FDA has set up a medical reporting program called Medwatch to track serious adverse events (1-800-FDA-1088). The manufacturer must report adverse drug reactions at quarterly intervals for the first 3 years after approval,  including a special report for any serious and unexpected adverse reactions.

Recent Developments in Drug Approval

The Food and Drug Administration Modernization Act of 1997 (FDAMA) extended the use of user fees and focused on streamlining the drug approval process.  In 1999, the 35 drugs approved by the FDA were reviewed in an average of 12.6 months, slightly more than the 12-month goal set by PDUFA.  This act also increased patient access to experimental drugs and facilitated an accelerated review of important new medications. The law ended the ban on disseminating information to providers about non-FDA-approved uses of medications. A manufacturer can now provide peer-reviewed journal articles about an off-label indication of a product if the company commits to filing a supplemental application to establish the use of the unapproved indication. As part of this process, the company must still conduct its own phase 4 study. As a condition for an accelerated approval, the FDA can require the sponsor to carry out postmarketing studies to confirm a clinical benefit and product safety. Critics contend the 1997 act compromises public safety by lowering the standard of approval.  Within a year after the law was passed, several drugs were removed from the market. Among these medications were mibefradil for hypertension, dexfenfluramine for morbid obesity, the antihistamine terfenadine, and bromfenac sodium for pain.  More recently, additional drugs including troglitazone were removed from the market. Although the increase in recalls might reflect the dramatic increase in drugs approved and launched, others argue that several safety questions were ignored.  Another concern was that many withdrawn drugs were me-too drugs which did not represent a noteworthy advance in therapy. Persons critical of the FDA believe changes in the approval process, such as allowing some new drugs to be approved based on only a single clinical trial, expanded use of accelerated approvals, and the use of surrogate end points, have created a dangerous situation.  Proponents of the changes in the approval process argue that there is no evidence of increased risk from the legislative changes,  and that these changes improve access to cancer patients and those with debilitating disease who were previously denied critical and lifesaving medications.

New drugs are an important part of modern medicine. Just a few decades ago, a disease such as peptic ulcers was a frequent indication for major surgery. The advent of new pharmacologic treatments has dramatically reduced the serious complications of peptic ulcer disease. Likewise, thanks to many new antiviral medications, the outlook for HIV-infected patients has improved dramatically. It is important that physicians understand the process of approving these new medications. Understanding the process can promote innovation, help physicians assess new products, underline the importance of reporting adverse drug events, and provide physicians with the information to educate patients about participating in a clinical trial.

Drug discovery


In the fields of medicinebiotechnology and pharmacologydrug discovery is the process by which new candidate medications are discovered.

Historically, drugs were discovered through identifying the active ingredient from traditional remedies or by serendipitous discovery. Later chemical libraries of synthetic small moleculesnatural products or extracts were screened in intact cells or whole organisms to identify substances that have a desirable therapeutic effect in a process known as classical pharmacology. Sincesequencing of the human genome which allowed rapid cloning and synthesis of large quantities of purified proteins, it has become common practice to use high throughput screening of large compounds libraries against isolated biological targets which are hypothesized to be disease modifying in a process known as reverse pharmacology.

 

Hits from these screens are then tested in cells and then in animals for efficacy. Even more recently, scientists have been able to understand the shape of biological molecules at the atomic level, and to use that knowledge to design (seedrug design) drug candidates.

Modern drug discovery involves the identification of screening hits, medicinal chemistry and optimization of those hits to increase the affinityselectivity (to reduce the potential of side effects), efficacy/potencymetabolic stability (to increase the half-life), and oral bioavailability. Once a compound that fulfills all of these requirements has been identified, it will begin the process of drug development prior to clinical trials. One or more of these steps may, but not necessarily, involve computer-aided drug design.

Despite advances in technology and understanding of biological systems, drug discovery is still a lengthy, “expensive, difficult, and inefficient process” with low rate of new therapeutic discovery.[1]In 2010, the research and development cost of each new molecular entity (NME) was approximately US$1.8 billion.[2] Drug discovery is done by pharmaceutical companies, with research assistance from universities. The “final product” of drug discovery is a patent on the potential drug. The drug requires very expensive Phase I, II and III clinical trials, and most of them fail. Small companies have a critical role, often then selling the rights to larger companies that have the resources to run the clinical trials.

Drug targets

The definition of “target” itself is something argued within the pharmaceutical industry. Generally, the “target” is the naturally existing cellular or molecular structure involved in the pathology of interest that the drug-in-development is meant to act on. However, the distinction between a “new” and “established” target can be made without a full understanding of just what a “target” is. This distinction is typically made by pharmaceutical companies engaged in discovery and development of therapeutics. In an estimate from 2011, 435 human genome products were identified as therapeutic drug targets of FDA-approved drugs.[3]

“Established targets” are those for which there is a good scientific understanding, supported by a lengthy publication history, of both how the target functions in normal physiology and how it is involved in human pathology. This does not imply that the mechanism of action of drugs that are thought to act through a particular established targets is fully understood. Rather, “established” relates directly to the amount of background information available on a target, in particular functional information. The more such information is available, the less investment is (generally) required to develop a therapeutic directed against the target.

The process of gathering such functional information is called “target validation” in pharmaceutical industry parlance. Established targets also include those that the pharmaceutical industry has had experience mounting drug discovery campaigns against in the past; such a history provides information on the chemical feasibility of developing a small molecular therapeutic against the target and can provide licensing opportunities and freedom-to-operate indicators with respect to small-molecule therapeutic candidates.

In general, “new targets” are all those targets that are not “established targets” but which have been or are the subject of drug discovery campaigns. These typically include newly discoveredproteins, or proteins whose function has now become clear as a result of basic scientific research.

The majority of targets currently selected for drug discovery efforts are proteins. Two classes predominate: G-protein-coupled receptors (or GPCRs) and protein kinases.

Screening and design

The process of finding a new drug against a chosen target for a particular disease usually involves high-throughput screening (HTS), wherein large libraries of chemicals are tested for their ability to modify the target. For example, if the target is a novel GPCR, compounds will be screened for their ability to inhibit or stimulate that receptor (see antagonist and agonist): if the target is a protein kinase, the chemicals will be tested for their ability to inhibit that kinase.

Another important function of HTS is to show how selective the compounds are for the chosen target. The ideal is to find a molecule which will interfere with only the chosen target, but not other, related targets. To this end, other screening runs will be made to see whether the “hits” against the chosen target will interfere with other related targets – this is the process of cross-screening. Cross-screening is important, because the more unrelated targets a compound hits, the more likely that off-target toxicity will occur with that compound once it reaches the clinic.

It is very unlikely that a perfect drug candidate will emerge from these early screening runs. It is more often observed that several compounds are found to have some degree of activity, and if these compounds share common chemical features, one or more pharmacophores can then be developed. At this point, medicinal chemists will attempt to use structure-activity relationships (SAR) to improve certain features of the lead compound:

  • increase activity against the chosen target
  • reduce activity against unrelated targets
  • improve the druglikeness or ADME properties of the molecule.

This process will require several iterative screening runs, during which, it is hoped, the properties of the new molecular entities will improve, and allow the favoured compounds to go forward to in vitro and in vivo testing for activity in the disease model of choice.
Amongst the physico-chemical properties associated with drug absorption include ionization (pKa), and solubility; permeability can be determined by PAMPA and Caco-2. PAMPA is attractive as an early screen due to the low consumption of drug and the low cost compared to tests such as Caco-2, gastrointestinal tract (GIT) and Blood–brain barrier (BBB) with which there is a high correlation.

A range of parameters can be used to assess the quality of a compound, or a series of compounds, as proposed in the Lipinski’s Rule of Five. Such parameters include calculated properties such as cLogP to estimate lipophilicity, molecular weightpolar surface area and measured properties, such as potency, in-vitro measurement of enzymatic clearance etc. Some descriptors such asligand efficiency[4] (LE) and lipophilic efficiency[5][6] (LiPE) combine such parameters to assess druglikeness.

While HTS is a commonly used method for novel drug discovery, it is not the only method. It is often possible to start from a molecule which already has some of the desired properties. Such a molecule might be extracted from a natural product or even be a drug on the market which could be improved upon (so-called “me too” drugs). Other methods, such as virtual high throughput screening, where screening is done using computer-generated models and attempting to “dock” virtual libraries to a target, are also often used.

Another important method for drug discovery is drug design, whereby the biological and physical properties of the target are studied, and a prediction is made of the sorts of chemicals that might (e.g.) fit into an active site. One example is fragment-based lead discovery (FBLD). Novel pharmacophores can emerge very rapidly from these exercises. In general, computer-aided drug design is often but not always used to try to improve the potency and properties of new drug leads.

Once a lead compound series has been established with sufficient target potency and selectivity and favourable drug-like properties, one or two compounds will then be proposed for drug development. The best of these is generally called the lead compound, while the other will be designated as the “backup”.

Historical background

The idea that effect of drug in human body are mediated by specific interactions of the drug molecule with biological macromolecules, (proteins or nucleic acids in most cases) led scientists to the conclusion that individual chemicals are required for the biological activity of the drug. This made for the beginning of the modern era in pharmacology, as pure chemicals, instead of crude extracts, became the standard drugs. Examples of drug compounds isolated from crude preparations are morphine, the active agent in opium, and digoxin, a heart stimulant originating from Digitalis lanata. Organic chemistry also led to the synthesis of many of the cochemicals isolated from biological sources.

Nature as source of drugs

Despite the rise of combinatorial chemistry as an integral part of lead discovery process, natural products still play a major role as starting material for drug discovery.[7] A report was published in 2007,[8] covering years 1981-2006 details the contribution of biologically occurring chemicals in drug development. According to this report, of the 974 small molecule new chemical entities, 63% were natural derived or semisynthetic derivatives of natural products. For certain therapy areas, such as antimicrobials, antineoplastics, antihypertensive and anti-inflammatory drugs, the numbers were higher. In many cases, these products have been used traditionally for many years.

Natural products may be useful as a source of novel chemical structures for modern techniques of development of antibacterial therapies.[9]

Despite the implied potential, only a fraction of Earth’s living species has been tested for bioactivity.

Plant-derived

Prior to Paracelsus, the vast majority of traditionally used crude drugs in Western medicine were plant-derived extracts. This has resulted in a pool of information about the potential of plant species as an important source of starting material for drug discovery. A different set of metabolites is sometimes produced in the different anatomical parts of the plant (e.g. root, leaves and flower), and botanical knowledge is crucial also for the correct identification of bioactive plant materials.

Microbial metabolites

Microbes compete for living space and nutrients. To survive in these conditions, many microbes have developed abilities to prevent competing species from proliferating. Microbes are the main source of antimicrobial drugs. Streptomyces species have been a valuable source of antibiotics. The classical example of an antibiotic discovered as a defense mechanism against another microbe is the discovery of penicillin in bacterial cultures contaminated by Penicillium fungi in 1928.

Marine invertebrates

Marine environments are potential sources for new bioactive agents.[10] Arabinose nucleosides discovered from marine invertebrates in 1950s, demonstrating for the first time that sugar moieties other than ribose and deoxyribose can yield bioactive nucleoside structures. However, it was 2004 when the first marine-derived drug was approved. The cone snail toxin ziconotide, also known as Prialt, was approved by the Food and Drug Administration to treat severe neuropathic pain. Several other marine-derived agents are now in clinical trials for indications such as cancer, anti-inflammatory use and pain. One class of these agents are bryostatin-like compounds,under investigation as anti-cancer therapy.

Chemical diversity of natural products

As above mentioned, combinatorial chemistry was a key technology enabling the efficient generation of large screening libraries for the needs of high-throughput screening. However, now, after two decades of combinatorial chemistry, it has been pointed out that despite the increased efficiency in chemical synthesis, no increase in lead or drug candidates has been reached.[8] This has led to analysis of chemical characteristics of combinatorial chemistry products, compared to existing drugs or natural products. The chemoinformatics concept chemical diversity, depicted as distribution of compounds in the chemical space based on their physicochemical characteristics, is often used to describe the difference between the combinatorial chemistry libraries and natural products. The synthetic, combinatorial library compounds seem to cover only a limited and quite uniform chemical space, whereas existing drugs and particularly natural products, exhibit much greater chemical diversity, distributing more evenly to the chemical space.[7] The most prominent differences between natural products and compounds in combinatorial chemistry libraries is the number of chiral centers (much higher in natural compounds), structure rigidity (higher in natural compounds) and number of aromatic moieties (higher in combinatorial chemistry libraries). Other chemical differences between these two groups include the nature of heteroatoms (O and N enriched in natural products, and S and halogen atoms more often present in synthetic compounds), as well as level of non-aromatic unsaturation (higher in natural products). As both structure rigidity and chirality are both well-established factors in medicinal chemistry known to enhance compounds specificity and efficacy as a drug, it has been suggested that natural products compare favourable to today’s combinatorial chemistry libraries as potential lead molecules.

Natural product drug discovery

Screening

Two main approaches exist for the finding of new bioactive chemical entities from natural sources.

The first is sometimes referred to as random collection and screening of material, but in fact the collection is often far from random in that biological (often botanical) knowledge is used about which families show promise, based on a number of factors, including past screening. This approach is based on the fact that only a small part of earth’s biodiversity has ever been tested for pharmaceutical activity. It is also based on the fact that organisms living in a species-rich environment need to evolve defensive and competitive mechanisms to survive, mechanisms which might usefully be exploited in the development of drugs that can cure diseases affecting humans. A collection of plant, animal and microbial samples from rich ecosystems can potentially give rise to novel biological activities worth exploiting in the drug development process. One example of a successful use of this strategy is the screening for antitumour agents by the National Cancer Institute, started in the 1960s. Paclitaxel was identified from Pacific yew tree Taxus brevifolia. Paclitaxel showed anti-tumour activity by a previously undescribed mechanism (stabilization of microtubules) and is now approved for clinical use for the treatment of lung, breast and ovarian cancer, as well as for Kaposi’s sarcoma. Early in the 21st century, Cabazitaxel (made by Sanofi, a French firm), another relative of taxol has been shown effective against prostate cancer, also because it works by preventing the formation of microtubules, which pull the chromosomes apart in dividing cells (such as cancer cells). Still another examples are: 1. Camptotheca (Camptothecin · Topotecan · Irinotecan · Rubitecan · Belotecan); 2. Podophyllum (Etoposide · Teniposide); 3a. Anthracyclines (Aclarubicin · Daunorubicin · Doxorubicin · Epirubicin · Idarubicin · Amrubicin · Pirarubicin · Valrubicin · Zorubicin); 3b. Anthracenediones (Mitoxantrone · Pixantrone).

Nor do all drugs developed in this manner come from plants. Professor Louise Rollins-Smith of Vanderbilt University‘s Medical Center, for example, has developed from the skin of frogs a compound which blocks AIDS. Professor Rollins-Smith is aware of declining amphibian populations and has said: “We need to protect these species long enough for us to understand their medicinal cabinet.”

The second main approach involves Ethnobotany, the study of the general use of plants in society, and ethnopharmacology, an area inside ethnobotany, which is focused specifically on medicinal uses.

Both of these two main approaches can be used in selecting starting materials for future drugs. Artemisinin, an antimalarial agent from sweet wormtree Artemisia annua, used in Chinese medicine since 200BC is one drug used as part of combination therapy for multiresistant Plasmodium falciparum.

Structural elucidation

The elucidation of the chemical structure is critical to avoid the re-discovery of a chemical agent that is already known for its structure and chemical activity. Mass spectrometry, often used to determine structure, is a method in which individual compounds are identified based on their mass/charge ratio, after ionization. Chemical compounds exist in nature as mixtures, so the combination of liquid chromatography and mass spectrometry (LC-MS) is often used to separate the individual chemicals. Databases of mass spectras for known compounds are available. Nuclear magnetic resonance spectroscopy is another important technique for determining chemical structures of natural products. NMR yields information about individual hydrogen and carbon atoms in the structure, allowing detailed reconstruction of the molecule’s architecture.

Business Insights’ drug discovery research stream critically analyzes the cutting edge technologies and novel approaches shaping the future of drug discovery.

Our analysis spans the entire drug discovery process, from target selection and validation to drug safety testing and clinical trial design, with assessment of both small-molecule and biologic modalities. Our independent experts highlight where the future opportunities lie and which companies are best positioned to take advantage.

The pharmaceutical industry is facing unprecedented pressure from a combination of factors: key product patent expiries, an increasingly demanding regulatory environment, declining R&D productivity, and escalating costs. The urgent need to combat these threats places a premium on scientific innovation, but innovation itself does not guarantee success. Achieving the required increase in drug discovery output will only be achieved by those making investments in the right diseases, biological targets, and therapeutic approaches, and the right technologies to expedite the process.

Typically research and drug discovery are not regulated at all. GLP starts with preclinical development, for example toxicology studies. Clinical trials are regulated by good clinical practice regulations and manufacturing through GMPs. There is a frequent misunderstanding that all laboratory operations are regulated by GLP. This is not true. For example, Quality Control laboratories in manufacturing are regulated by GMPs and not by GLPs. Also Good laboratory Practice regulations are frequently mixed up with good analytical practice. Applying good analytical practices is important but not sufficient, as we will see in this presentation. When small quantities of active ingredients are prepared in a research or development laboratory for use in samples for clinical trials or finished drugs, that activity has be covered by GMP and not by GLP.

Part 11 is FDA’s regulation on electronic records and signatures and applies for electronic records or to computer systems in all FDA regulated areas. For example, it applies for computers that are used in GLP studies.

Characteristic for GLPs is that they are study based where as GMPs are processed based.

Independent from Location and Duration of a Study

GLPs regulate all non-clinical safety studies that support or are intended to support applications for research or marketing permits for products regulated by the FDA, or by similar other national agencies. This includes drugs for human and animal use but also aroma and color additives in food, biological products and medical devices. The duration and location of the study is of no importance. For example GLP applies to short term experiments as well as to long term studies. And if a pharmaceutical company subcontracts part of a study to a university, that university still must comply with the same requirements as the sponsor company. Some laboratories tried to get away from GLP through outsourcing, but I can tell you this does not work.

Facility Management and Other Personnel

Qualification of Personnel

Like all regulations also GLPs have chapters on personnel.

The assumption is that in order to conduct GLP studies with the right quality a couple of things are important:* Number one there should be sufficient people and second, the personnel should be qualified.

The FDA is not specific at all what type of qualification or education people should have. Qualification can come from education, experience or additional trainings, but it should be documented. This also requires a good documentation of the job descriptions, the tasks and responsibilities.

Facility management

Responsibilities of facility management are well defined. They include to designate a study director and also to monitor the progress of the study and if it is not going well to replace the study director.

The management is responsible for many things, basically they should assure that a quality assurance unit is available, test and control articles are characterized, and that sufficient qualified personnel is available for the study.

Because it is obvious that management can not take care personally about all this they have to rely on other functions, for example GLPs require that the QA should give a regular report on the compliance status of the study.

Small Molecule Drugs versus Biomolecular Drugs (Biologics)

Biotechnology has created a broad range of therapies, including vaccines, cell or gene therapies, therapeutic protein hormones, cytokines and tissue growth factors, and monoclonal antibodies.  In this discussion we will focus on the categories of biomolecular drugs that are presently managed by the FDA Center for Drugs Evaluation and Research (CDER): monoclonal antibodies, cytokines, tissue growth factors and therpeutic proteins. Some of the data that we will show includes all biologics.  Modern biomolecular drugs arise through the processes of genetic engineering.

It has been a little over thirty years since human insulin received U.S. approval (1982) as the first genetically engineered biomolecular drug.  Since then biomolecular drugs have become a major force in the bio/pharmaceutical industry.  As seen in Table 1, based on worldwide sales, eight out of the top 20 biopharmaceuticals in 2012 were Biomolecular Drugs. (Ref 1, 2)  In fact seven of the top 10 were biomolecular drugs!

Table 1, Eight of the Top Twenty Biopharmaceuticals Worldwide in 2012 are BiomolecularDrugs (Data from references  US Ranking.  Copaxone ranked 9th in US Sales (Ref 3), and was unranked in worldwide sales.

This may come as a surprise to many in the U.S. where biomolecular drugs have yet to achieve such a prominent stature. In 2012 Humira, Enbrel, Remicade, Neulasta and Rituxan were in the top 10 drugs based on U.S. sales, but the small molecules Nexium, Abilify, Crestor, Advair, and Cymbalta were the top five.  None of the biomolecular drugs were in the top 10 in the U.S. in 2010. (How the rankings of drugs in the U.S. could be so different from the rest of the world is a whole other discussion.) In any event, the rise of biomolecular drugs into the top tier is a recent phenomenon.

Let us compare and contrast these two types of drugs – small molecule and biomolecular drugs, and see how the Industry deals with two seemingly very different types of drugs.

The bio/pharmaceutical industry embraces the discovery and development of both small molecule drugs (also referred to as New Chemical Entities or NCEs) and biomolecular drugs, also called biologics (also referred to as New Biological Entities or NBEs).  Small Molecule and biomolecular drugs can take on different names over the lifetime of drug discovery and development and marketing, as shown in Fig 1 and described in Ref 5.

Figure 1, Small Molecules and Biomolecules can take on different names over the lifetime of drug discovery and development and marketing.  Biosimilars are also referred to as Follow-on Biologics. Phase length is not implied by the size of stage marker. *NME relates to the first approvable drug as opposed to second indications or new formulations.   The application for a generic small molecule is an “Abbreviated New Drug Application” (ANDA) which doesn’t require clinical trials to prove equivalency.  Processes for biosimilars or follow-on biologics are in the discussion stage.

A biotechnology company or a biopharmaceutical company tends to focus on the discovery and development of biomolecular drugs. A bio/pharmaceutical company will have the resources to discover and develop both types of drugs, NCEs and NBEs.

Since the early ‘80s the number of INDs per year from NCEs has leveled off while the INDs from NBEs have increased and helped maintain an increasing number of INDs/year (up to 1993). Trusheim et al. and others have studied the number of new small molecule drug approvals (NMEs) compared to new biologic drug approvals (new BLAs) in the period between 1988-2008, Table 2.

Table 2, Numbers of New Small Molecule Drug Approvals per Year (NMEs) Compared to New Biologic Drug Approvals (new BLAs) 1988-2008.  Biologics here are not restricted to monoclonal antibodies, cytokines, tissue growth factors and therapeutic proteins.  Last line* shows therapeutic proteins and Mabs from Reichert 8  We extended the tally by Reichert beyond 2003 by adding our own count of Mab and therapeutic protein new BLAs from annual FDA reports through 2008.  Mullard and Kneller  recently published counts of NMEs and New BLAs which differ somewhat from Trusheim or Reichert .  We are not in a position to rectify the differences, except to offer a potential explanation – certain small peptide and protein drugs may be considered either biologics or small molecules (Kneller considered such drugs to be biologics).

The analysis by Trusheim et al. was not restricted to monoclonal antibodies, cytokines, tissue growth factors and therapeutic proteins.  They found that from 1988 to 2003 the industry averaged 34 NMEs and new BLAs per year, whereas from 2004-2008 the industry averaged only 21 NMEs and new BLAs per year.  Within those two periods the percentage of new BLAs was quite similar (31% vs 32%).    To add some perspective we include the mabs and therapeutic proteins counted by Reichert.  By the numbers, all biologics are making a substantial contribution to the number of new drugs approved per year.

By 1997 worldwide sales of biologics were over $7 billion dollars.  The global sales of biologics have continued to rise – monoclonal antibodies alone in 2006 totaled $4.7 billion dollars.

A popular misconception is that in the early days most of the new biologics were discovered and developed within biotech companies.  Certainly few of the classically NCE-oriented companies entered the NBE arena – The pharmaceutical companies J&J (Ortho Biotech), Lilly and Roche were early players, getting BLAs approved in the ‘80s, Table 3.

Table 3, Early Biotech and Drug Company Biologics Approvals (without Diagnostics)

But 50% of the BLAs in the 80’s came from drug companies.  In the ‘90s, 52% of the BLAs came from drug companies (data from Table 3).  Thus while  a lot of investment may have gone into biotech startups, it was the previous experience of the drug companies with bringing drugs to market that made them at least equal partners in that aspect of biomolecular R&D.  Still only 17 drug companies and 16 biotech companies got BLAs in the ‘80s and ‘90s which is a small subset of the pharmaceutical industry.  By 1998 the PhRMA determined that more than 140 US-based companies were engaged in biomolecular drug development.  Most likely many more pharmaceutical companies were investing in biotech in that period.  The investment in biologics was enormous and the payout uncertain. As with the discovery and development of any drug it took years before the new biotechs achieved their first BLA, over 14 years on average, Table 4.

Table 4 Early Biotech Approvals – Years Since Founding.

While many of the discoveries of new biologics continue to originate in biotech companies, the clinical development of new biologics are increasingly supported by large pharma which had been NCE-oriented, Table 3.

In recent years most of the large pharma have gained an expertise in biologics through entry into field, and also through acquisitions and are now bio/pharmaceutical companies, Table 5.. The acquisition of Genzyme by Sanofi-Aventis is a most recent example.

Table 5, Notable Acquisitions and Partnerships involving Biologics

A recent collaborative study by Deloitte and Thomson Reuters showed that the twelve top bio/pharmaceutical companies all had biologics in their late stage portfolios, ranging from 21-66% of their portfolios (avg. 39%)

Prior to the ‘80s there were sufficiently few biomolecular drugs that the very term “pharmaceutical” or “drug” was taken to mean small molecule. With the exception of insulin, the few biomolecules approved for human use were administered by a trained health practitioner and were often considered “therapies”. Thus one may see the comparison of “small molecule drugs (or pharmaceuticals) versus large molecule therapies”. Here we will consider a large molecule therapy that is regulated by CDER to be a biomolecular type of drug or pharmaceutical.

The term for first small molecule drug approval, or New Molecular Entity (NME) could in theory be applied to first biologic approval, but because NME has long been associated with small molecules it is not being associated with first biologic approval – which is simply called a new BLA.

On March 23, 2010 President Obama signed into law the Biologics Price Competition and Innovation Act (BPCIA) which provides for biosimilar biologic drug approvals, as part of the omnibus health care bill. As the FDA develops guidelines for biosimilar approvals and begins to review applications for biosimilars, biologics will begin to enter the large generics market in the U.S.

The Processes that Give Rise to Biomolecular Drugs. Human insulin was the first recombinant biopharmaceutical approved in the U.S. in 1982. Prior to that protein products approved for use in humans were extracted from natural sources. It is beyond the scope of this website to delve into the details of the processes that give rise to biomolecular drugs or small molecule drugs. The following are good general references that cover the processes involved in the discovery and development of both small molecule drugs and biomolecular drugs.

Understanding the Differences and Similarities Between Small Molecules and Biologics. Now, more than ever, anyone interested in understanding the bio/pharmaceutical industry will need to understand both the differences and similarities between small molecules and biologics and their discovery and development as drugs.

1. How Do Small Molecule Drugs Differ from Biomolecular Drugs?

One has only to consider the size of biologics to recognize that the technologies that give rise to biomolecular drugs must be considerably different from the classical small molecule drugs. Genentech equates the difference between aspirin (21 atoms) and an antibody (~25,000 atoms) to the difference in weight between a bicycle (~20 lbs) and a business jet (~30,000 lbs).19 We will consider how they differ with respect to distribution, metabolism, serum half-life, typical dosing regimen, toxicity, species reactivity, antigenicity, clearance mechanisms, and drug-drug interactions (especially small molecule/biologic drug interactions).

A project leader who has worked in one field and is now facing the prospect of leading a project in the other field should become familiar with these differences as they will give rise to issues that the project leader may not have faced before.

2. Historical Changes in FDA Biologics Oversite in Response to the Biotech Boom

Prior to the ‘80s biologics were extracted from natural sources and required different regulatory oversight than that of small molecule drugs. Since then, the production of biologics shifted to recombinant proteins, which involved more consistent production processes, and the number of approvals has risen dramatically. We will review how FDA oversight has changed to accommodate the boom in biotechnology.

3. Overall Clinical Success Rates of Biologics versus Small Molecules

Only a few biomolecular drugs were approved in the U.S. per year until 1997, when eight were approved in one year. From that time onward approvals have been over a half dozen per year. There are now sufficient numbers of biomolecular drugs to begin to allow cross-industry comparisons of metrics between small molecule and biomolecular drugs. We compare the various studies over the last twenty years that have been published on overall clinical success rates for both small molecules and biologics from Dimasi and Reichert at the Tufts Center for the Study of Drug Development, Grabowski at Duke University and others. Since these metrics have changed over time we provide era-by-era comparisons, wherever possible.

4. Stage Related Success Rates and Cycle Times for Small Molecules vs Biologics

We also examine the success rates and cycle times for the various stages of clinical development for both small molecules and biologics. Again, since these metrics have changed over time we provide era-by-era comparisons where ever possible.

5. Comparative Cost of R&D for Biologics Versus Small Molecules

The differences in success rates and cycle times noted above have a knock-on effect on the cost of R&D for biomolecules over small molecules.

6. Are Peptide Drugs Small Molecules or Biologics?

This hybrid class of drugs tends to be considered a class of biologics, especially because oral activity is rare amongst peptide drugs. But we show that peptides truly bridge the gap between small molecules and biologics, in terms of physical properties, range of therapy areas and means of production. (The processes employed in producing peptide drugs vary, from the chemical processes used for the smaller peptide drugs to recombinant technologies used for the larger peptide drugs.)

7. Biosimilar and Biobetter Macromolecules versus Generic Small Molecules

Those early biotechnology wonder drugs are now facing patent expiration. The industry has been engaged in an intense debate as to how a generic biomolecular drug, aka biosimilar or follow-on biologic) can be approved and managed by the same regulations that govern generic small molecule drugs. The issues are complex, arising out of the considerable differences between small molecules and biologics.  More recently big biopharma have taken an interest biobetters. A biobetter is a biologic which has a purposefully modified structure from the original that allows it to be afforded patent protection and pricing strategy akin to the original biologic because it is in some way “better” than the original.

8. Discovery and Preclinical Stages – Where the Technologies Differ the Most– Small Molecules vs Biologics

It is in the stages of Discovery and Preclinical Development where the technologies are most different. We outline the differences and similarities between small molecules and biologics in Lead Discovery, Lead Optimization and Preclinical Development.

9. Small Molecule and Biologics Approvals by Therapy Areas

With technological advances in the discovery and development of biologics most therapy areas (80%) are now amenable to either a small molecule or biologic strategy.

10. Managing Small Molecule & Biomolecular Drug R&D in the Same Company

The bio/pharmaceutical company that has the resources to discover and develop both types of drugs will inevitably face the challenge of organizing these activities. We argue that the fact that both small molecules and biologics can be managed with the same milestones and stages argues for treating both strategies in the same portfolio. The savvy portfolio manager will understand the differences and ensure the differences are transparent from a portfolio perspective.

Applications in Drug Discovery and Development

Several phase in drug discovery and development can be supported by metabonomics. In a very early phase, metabonomics can help in selecting drug candidates by monitoring toxicity. On the one hand the protocols of candidate selection studies are very simple, rendering metabonoic analyses very challenging in terms of number of samples. On the other hand rather high doses can result in clear metabonomic effects, which can be used for outruling candidates. In later clinical phases, metabonomics can help in an advanced profiling of a drug candidate. Thereby metabonomics can be added to acute and chronic GLP studies. As these studies are highly controled and as typically several sampling time points are available, detailed mechanistic investations can be performed. These studies also allow looking for bridging biomarker and effects, which can be monitored in clinical phase I studies later on. In clinical studies metabonomics can be used for several purposes, such as monitoring safety biomarkers, for monitoring the efficacy of therapy, for diagnosis and for stratification of patients.

References

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  5.  Ryckmans, T. et al. (2009). “Rapid assessment of a novel series of selective CB2 agonists using parallel synthesis protocols: A Lipophilic Efficiency (LipE) analysis”. Bioorg. Med. Chem. Lett. 19 (15): 4406–4409. doi:10.1016/j.bmcl.2009.05.062PMID 19500981.
  6.  Leeson, P. D. et al. (2007). “The influence of drug-like concepts on decision-making in medicinal chemistry”. Nature Reviews Drug Discovery 6 (11): 881–890. doi:10.1038/nrd2445.PMID 17971784.
  7.  Feher M, Schmidt JM (2003). “Property distributions: differences between drugs, natural products, and molecules from combinatorial chemistry”. J Chem Inf Comput Sci 43 (1): 218–27.doi:10.1021/ci0200467PMID 12546556.
  8.  Newman DJ, Cragg GM (March 2007). “Natural products as sources of new drugs over the last 25 years”. J. Nat. Prod. 70 (3): 461–77. doi:10.1021/np068054vPMID 17309302.
  9.  von Nussbaum F, Brands M, Hinzen B, Weigand S, Häbich D (August 2006). “Antibacterial natural products in medicinal chemistry–exodus or revival?”. Angew. Chem. Int. Ed. Engl. 45 (31): 5072–129. doi:10.1002/anie.200600350PMID 16881035. “The handling of natural products is cumbersome, requiring nonstandardized workflows and extended timelines. Revisiting natural products with modern chemistry and target-finding tools from biology (reversed genomics) is one option for their revival.”
  10.  John Faulkner D, Newman DJ, Cragg GM (February 2004). “Investigations of the marine flora and fauna of the Islands of Palau”. Nat Prod Rep 21 (1): 50–76. doi:10.1039/b300664f.PMID 15039835.

  • Gad, Shayne C. (2005). Drug discovery handbook. Hoboken, N.J: Wiley-Interscience/J. Wiley. ISBN 0-471-21384-5.
  • Madsen, Ulf; Krogsgaard-Larsen, Povl; Liljefors, Tommy (2002). Textbook of drug design and discovery. Washington, DC: Taylor & Francis. ISBN 0-415-28288-8.

How to Handle Drug Polymorphs… Case Study of Trelagliptin Succinate


Pharmaceutical API Polymorphs… case study of Trelagliptin
CASE STUDY WITH..Compound I having the formula
Figure imgf000073_0001
Links
WO2008067465A1 OR US8084605  IS THE PATENT USED AND WITH FORM “A” AND AMORPHOUS FORM
Active pharmaceutical ingredients (APIs), frequently delivered to the patient in the solid-state as part of an approved dosage form, can exist in such diverse solid forms as polymorphs, pseudopolymorphs, salts, co-crystals and amorphous solids. Various solid forms often display different mechanical, thermal, physical and chemical properties that can remarkably influence the bioavailability, hygroscopicity, stability and other performance characteristics of the drug.
Hence, a thorough understanding of the relationship between the particular solid form of an active pharmaceutical ingredient (API) and its functional properties is important in selecting the most suitable form of the API for development into a drug product. In past decades, there have been significant efforts on the discovery, selection and control of the solid forms of APIs and bulk drugs.

If you’re involved in late drug discovery, API manufacture, drug product formulation, clinical material production, or manufacture of final dosage form, a basic understanding and awareness of solid form issues could save you a great deal of difficulty, time, and money during drug development.

 
What is polymorphism?
Polymorphs are crystalline materials that have the same chemical composition but different molecular packing. The concept is well demonstrated by the different crystalline forms of carbon. Diamond, graphite, and fullerenes are all made of pure carbon, but their physical and chemical properties vary drastically. Polymorphs are one type of solid form. Other solid form types include solvates, hydrates, and amorphous forms.
Solvates are crystalline materials made of the same chemical substance, but with molecules of solvent regularly incorporated into a unique molecular packing. When water is the solvent, these are called hydrates. An amorphous form of a substance has the same chemical composition, but lacks the long-range molecular order of a crystalline form of the same substance. Many organic and inorganic compounds, including APIs, can exist in multiple solid forms.
Some APIs may have only one or two known solid forms. Others may exist in twenty different forms, each having different physical and chemical properties.
Solid form screening, including salt, polymorph, cocrystal and amorphous solid dispersions, is vitial for successful pharmaceutical development. With an increase in the size and complexity of the molecules that enter into drug development, companies face a larger number of compounds that are either poorly soluble, difficult to crystallize or problematic with respect to desired physical chemical properties hindering successful drug development.
Crystallics has an extensive track record in executing solid state research studies and its research team has a broad expertise in identifying new crystal forms as well as in solving problems related to polymorphism and crystallization.

Investigational new drug, writing an application for clinical trial authorization, permission marketing …The control of polymorphism in drug candidates is now ubiquitous.

Links

READ………….An Overview of Solid Form Screening During Drug Development, http://www.icdd.com/ppxrd/10/presentations/PPXRD-10_Ann_Newman.pdf

ANN NEWMAN

When addressing the subject of polymorphism, the first reference that comes to mind is that of the occurred during the manufacture of ritonavir incident. Abbott molecule inhibitor of HIV protease marketed as Norvir, is a cautionary example of the challenges of polymorphism. 

Indeed, during the production of ritonavir in 1997, a new polymorph unmarked emerged. Its precipitation and unexpected outbreak led to the cessation of the production of Norvir and seriously compromise the process. The incident has deeply marked the pharmaceutical industry.

It is ironic that the process used to discover pharmaceutical drug targets is the same one that decreases the actual efficacy of those drugs once ingested. If you remember from basic chemistry, there are compounds that exist in highly ordered crystalline states and those that remain in amorphous form.

The discovery of drug targets has often been accomplished through X-ray crystallography, which requires a sample (for example, of a defective enzyme linked to cancer or high cholesterol) to be crystallized so that the diffraction patterns can be made sense of. Scientists may spend years trying to crystallize one molecule or compound so that they can identify regions that, for example, may be blocked by pharmaceuticals.

However, when it comes to the molecular arrangement of those pharmaceuticals, crystallization actually decreases their bioavailability and solubility. Thus, it may be better for these drugs to be in amorphous form. Pierric Marchand, general manager of the company Holodiag, dedicated to the study and characterization of solid state, summarizes that ” today, it is not reasonable to not worry about the problem of polymorphism ” .

” In recent years, manufacturers have realized the essential side of expertise , “says Jean-Rémi David, commercial director Calytherm. The services company specializing in the field of physico-chemical analysis, based in Herault, has just relocated last year in supporting pharmaceutical development to meet demand. ” This is a concern for all deal with potential impacts on the effectiveness or the formulation , “says Stéphane Suchet, quality manager in the group of fine and specialty chemicals Axyntis.

Polymorphic forms are the amorphous and crystalline forms such as hydrate or solvate forms. When a molecule of interest exists in polymorphic forms, it is called polymorphism, according to the definition of the FDA (Food and Drug Administration).

Polymorphism is present at all stages of development of a drug from research to marketing. ” Keep in mind that organic molecule loves to polymorphism , “says Marchand Pierric. However, for a marketing authorization for example, must learn the criteria for the polymorphism of the molecule. ” In terms of the formulation, for example we can check whether the selected polymorphism is unchanged , “explains Pierric Marchand.

A significant influence on several levels  Because the consequences of polymorphism are multiple. ” They are at three levels: bioequivalence, manufacturability and stability “lists Fabienne Lacoulonche, founder and scientific director of Calytherm.In terms of bioequivalence, different polymorphic forms may have different properties of solubility and dissolution rate … ” For poorly soluble active ingredients, you can have much more bioavailable than other crystalline forms , “Fabienne Lacoulonche information.

In terms of manufacturability, some parameters such as temperature, moisture can lead to changes in the crystalline form. ” The complexity is to anticipate changes polymorphism, both at laboratory scale, pilot and industrial , “adds the founder of Calytherm. Finally, polymorphism plays on stability. Active ingredient or finished product, are subjected to stability studies in this direction. ” When the molecule is identified, we try to highlight the existence of several forms of polymorphism, explains Stéphane Suchet (Axyntis) 

When developing a new substance, the assessment is systematic . ” Isolation of crystals from a screening is carried out in different solvents by various analytical techniques. Ideally, it will be concluded the absence of polymorphism. ” But if different polymorphic forms are present, we rework the terms of our crystallization process to control the formation of the same polymorph reproducibly ideally form the thermodynamically more stable , “says Stéphane Suchet. X-ray diffraction and other thermal analysis ”

The ICH guidelines provide decision trees to guide the industry in controlling polymorphism says Fabienne Lacoulonche (Calytherm.) We use it for writing the CTD (Common Technical Document) .

“Polymorphism is a phenomenon” complex and difficult to control, because the crystallization is dependent on many parameters , she develops. must understand the maximum . ” For this, several analytical methods are available to industry. The main technique is the X-ray diffraction ” It is a robust, rapid, which allows to characterize the different polymorphs , “summarizes Pierric Marchand (Holodiag).Non-destructive, it can work both on small quantities on large samples. Temperature and atmosphere are controlled, and analytical capabilities are broad.

But if this technique indispensable allows for routine and development, it is not sufficient in itself. Just to add a battery of additional tests, thermal analysis. ” It takes coupling methods “ confirms Fabienne Lacoulonche (Calytherm). The X-ray diffraction is a method of choice, but sometimes it is not sufficient.

The coupling with a thermal analysis method (technical ATG, or DSC thermal analysis, differential scanning calorimetry or thermomicroscopique) allows to distinguish between two polymorphic whose RX diffractograms obtained are comparable.

TGA can be coupled with IR or mass spectrometry, DSC with RX. Raman spectroscopy is also part of complementary methods. ” The difficulty increases when we want to characterize the shape of the active ingredient in the finished product , says Fabienne Lacoulonche. example, by X-ray diffraction, the peaks related to the active ingredient in the diffractogram of the finished product may be masked by those excipients: it is then necessary to use other methods, such as Raman microscopy. “In general, a single method of analysis is not sufficient to characterize the polymorphism of an active substance in the active substance or finished product: the complementarity of different methods that will conclude precisely on the polymorphism of a crystalline substance.

In addition, ” the diffractometer remains an expensive device, which requires installation in an air-conditioned and a cooling room , “says Marchand Pierric (Holodiag). To this is added the need to have expertise and qualified personnel to carry out the analyzes. ” We must master these techniques and the ability to interpret the results , “says Jean-Rémi David (Calytherm). However, polymorphism is a “problem well under control , “said Stéphane Suchet (Axyntis),” systematically evaluated although it is however not always immune to miss a polymorphic form, knowing that the screening performed in the development can never be completely comprehensive … ”

FDA

FDA may refuse to approve an ANDA referencing a listed drug if the application contains insufficient information to show that the drug substance is the “same” as that of the reference listed drug. A drug substance in a generic drug product is generally considered to be the same as the drug substance in the reference listed drug if it meets the same standards for identity.

In most cases, the standards for identity are described in the USPalthough FDA may prescribe additional standards when necessary. Because drug product performance depends on the product formulation, the drug substance in a proposed generic drug product need not have the same physical form (particle size, shape, or polymorph form) as the drug substance in the reference listed drug. An ANDA applicant is required to demonstrate that the proposed product meets the standards for identity, exhibits sufficient stability and is bioequivalent to the reference listed drug.

Links

FDA PRESENTATION……polymorphs and co-crystals – ICDD      Regulatory Considerations on Pharmaceutical Solids: Polymorphs/Salts and Co-Crystals.. THIS IS A MUST READ ITEM

Over the years FDA has approved many generic drug products based upon a drug substance with different physical form from that of the drug substance in the respective reference listed drug (e.g., warfarin sodium, famotidine, and ranitidine). Also many ANDAs have been approved in which the drug substances differed from those in the corresponding reference listed drugs with respect to solvation or hydration state (e.g., terazosin hydrochloride, ampicillin, and cefadroxil). Several regulatory documents and literature reports (67-69) address issues relevant to the regulation of polymorphism.

The concepts and principles outlined in these are applicable for an ANDA. However, certain additional considerations may be applicable in case of ANDAs. Often at the time FDA receives an ANDA a monograph defining certain key attributes of the drug substance and drug product may be available in the Unites States Pharmacopoeia (USP). These public standards play a significant role in the ANDA regulatory review process and in case of polymorphism, when some differences are noted, lead to additional requirements and considerations.

This commentary is intended to provide a perspective on polymorphism in pharmaceutical solid in the context of ANDAs. It highlights major considerations for monitoring and controlling drug substance polymorphs and describes a framework for regulatory decisions regarding drug substance “sameness” considering the role and impact of polymorphism in pharmaceutical solids.

Since polymorphs exhibit certain differences in physical (e.g., powder flow and compactability, apparent solubility and dissolution rate) and solid state chemistry (reactivity) attributes that relate to stability and bioavailability it is essential that the product development and the FDA review process pay close attention to this issue.

This scrutiny is essential to ensure that polymorphic differences (when present) are addressed via design and control of formulation and process conditions to physical and chemical stability of the product over the intended shelf-life, and bioavailability/bioequivalence.

Most pharmaceuticals are distributed as solid doseages. In order to take action, they must dissolve in the gut and be absorbed into the blood stream. In many cases, the rate at which the drug dissolves can limit its effectiveness. Pharmaceutical compounds can be packed into more than one arrangement in the solid states known as polymorphs. Rapid and efficient methods of polymorph formation can be used to increase drug efficacy and shelf life.

Regulatory agencies worldwide require that, as part of any significant filing, a company has to demonstrate that it has made a reasonable effort to identify the polymorphs of their drug substance and has checked for polymorph interconversions. Due to the unpredictable behaviour of polymorphs and their respective differences in physicochemical properties, companies also have to demonstrate consistency in manufacturing between batches of the same product. Proper understanding of the polymorph landscape and nature of the polymorphs will contribute to manufacturing consistency.

Links

POLYMORPHISM AND PATENTS http://www.collegio.unibo.it/uploads/ideas/joelbernstein.pdf  A MUST CLICK FOR PHARMA CHEMISTS

Triclinic Labs approach to solid-state (solid form) screening and selection for optimal properties of an active pharmaceutical ingredient

Links

READ………..High-throughput crystallization: polymorphs, salts, co-crystalsand solvates of pharmaceutical solidshttp://citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.85.5397&rep=rep1&type=pdf

Definitions

“Crystalline”, as the term is used herein, refers to a material, which may be hydrated and/or solvated, and has sufficient ordering of the chemical moiety to exhibit a discernable diffraction pattern by XRPD or other diffraction techniques. Often, a crystalline material that is obtained by direct crystallization of a compound dissolved in a solution or by interconversion of crystals obtained under different crystallization conditions, will have crystals that contain the solvent used in the crystallization, termed a crystalline solvate. Also, the specific solvent system and physical embodiment in which the crystallization is performed, collectively termed crystallization conditions, may result in the crystalline material having physical and chemical properties that are unique to the crystallization conditions, generally due to the orientation of the chemical moieties of the compound with respect to each other within the crystal and/or the predominance of a specific polymorphic form of the compound in the crystalline material.

Depending upon the polymorphic form(s) of the compound that are present in a composition, various amounts of the compound in an amorphous solid state may also be present, either as a side product of the initial crystallization, and/or a product of degradation of the crystals comprising the crystalline material. Thus, crystalline, as the term is used herein, contemplates that the composition may include amorphous content; the presence of the crystalline material among the amorphous material being detectably among other methods by the composition having a discernable diffraction pattern.

The amorphous content of a crystalline material may be increased by grinding or pulverizing the material, which is evidenced by broadening of diffraction and other spectral lines relative to the crystalline material prior to grinding. Sufficient grinding and/or pulverizing may broaden the lines relative to the crystalline material prior to grinding to the extent that the XRPD or other crystal specific spectrum may become undiscernable, making the material substantially amorphous or quasi-amorphous. Continued grinding would be expected to increase the amorphous content and further broaden the XRPD pattern with the limit of the XRPD pattern being so broadened that it can no longer be discerned above noise. When the XRPD pattern is broadened to the limit of being indiscernible, the material may be considered no longer a crystalline material, but instead be wholly amorphous. For material having increased amorphous content and wholly amorphous material, no peaks should be observed that would indicate grinding produces another form.

“Amorphous“, as the term is used herein, refers to a composition comprising a compound that contains too little crystalline content of the compound to yield a discernable pattern by XRPD or other diffraction techniques. Glassy materials are a type of amorphous material. Glassy materials do not have a true crystal lattice, and technically resembling very viscous non-crystalline liquids. Rather than being true solids, glasses may better be described as quasi-solid amorphous material. “Broad” or “broadened”, as the term is used herein to describe spectral lines, including XRPD, NMR and IR spectroscopy, and Raman spectroscopy lines, is a relative term that relates to the line width of a baseline spectrum. The baseline spectrum is often that of an unmanipulated crystalline form of a specific compound as obtained directly from a given set of physical and chemical conditions, including solvent composition and properties such as temperature and pressure.

For example, broadened can be used to describe the spectral lines of a XRPD spectrum of ground or pulverized material comprising a crystalline compound relative to the material prior to grinding. In materials where the constituent molecules, ions or atoms, as solvated or hydrated, are not tumbling rapidly, line broadening is indicative of increased randomness in the orientation of the chemical moieties of the compound, thus indicative of an increased amorphous content. When comparisons are made between crystalline materials obtained via different crystallization conditions, broader spectral lines indicate that the material producing the relatively broader spectral lines has a higher level of amorphous material.

“About” as the term is used herein, refers to an estimate that the actual value falls within ±5% of the value cited. “Forked” as the term is used herein to describe DSC endotherms and exotherms, refers to overlapping endotherms or exotherms having distinguishable peak positions

.

Classes of multicomponent pharmaceutical materials. (a) Schematic of crystalline materials showing neutral and charged species. The red box indicates polymorphs are possible for all the multicomponent crystals contained within the box (adapted from Reference 7). (b) Schematic of amorphous solid dispersions showing binary, ternary, and quaternary possibilities for polymers and surfactants. Other solubilization techniques using cyclodextrins and phospholipids are included for completeness but have a different mechanism for solubilization when compared to polymer and surfactant systems.

The red box indicates that properties can change with water or solvent content. General methods for precipitating and crystallizing a compound may be applied to prepare the various polymorphs described herein. These general methods are known to those skilled in the art of synthetic organic chemistry and pharmaceutical formulation, and are described, for example, by J. March, “Advanced Organic Chemistry: Reactions, Mechanisms and Structure ” 4th Ed. (New York: Wiley-Interscience, 1992).

In general, a given polymorph of a compound may be obtained by direct crystallization of the compound or by crystallization of the compound followed by inter-conversion from another polymorphic form or from an amorphous form. Depending on the method by which a compound is crystallized, the resulting composition may contain different amounts of the compound in crystalline form as opposed to as an amorphous material.

Also, the resulting composition may contain differing mixtures of different polymorphic forms of the compound. Compositions comprising a higher percentage of crystalline content {e.g., forming crystals having fewer lattice defects and proportionately less glassy material) are generally prepared when using conditions that favor slower crystal formation, including slow solvent evaporation and those affecting kinetics.

Crystallization conditions may be appropriately adjusted to obtain higher quality crystalline material as necessary. Thus, for example, if poor crystals are formed under an initial set of crystallization conditions, the solvent temperature may be reduced and ambient pressure above the solution may be increased relative to the initial set of crystallization conditions in order to slow down crystallization. Precipitation of a compound from solution, often affected by rapid evaporation of solvent, is known to favor the compound forming an amorphous solid as opposed to crystals. A compound in an amorphous state may be produced by rapidly evaporating solvent from a solvated compound, or by grinding, pulverizing or otherwise physically pressurizing or abrading the compound while in a crystalline state.

Seven crystalline forms and one amorphous solid were identified by conducting a polymorph screen (Example 3). Described herein are Form A, Form B, Form C, Form D, Form E, Form F, Form G, and Amorphous Form of Compound I. Where possible, the results of each test for each different polymorph are provided. Forms A, C, D and E were prepared as pure forms. Forms B, F, and G were prepared as mixtures with Form A.
Various tests were performed in order to physically characterize the polymorphs of Compound I including X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), hot stage microscopy, Fourier transform infrared spectroscopy (FT-IR), Fourier transform Raman spectrometry, linked thermogravimetric-infrared spectroscopy (TG-IR), solution proton nuclear magnetic resonance (1H-NMR), solid state 13carbon nuclear magnetic resonance (13C-NMR), and moisture sorption and desorption analysis (M S/Des).

 

Salt screening

Physicochemical properties of drug substances, such as solubility, dissolution rate, and physicochemical stability can be altered significantly by salt formation. Consequently, important properties of the drug product such as bioavailability or shelve life can be radically influenced. Crystallics’ technology platform for crystallization screening accommodates salt screening studies using only minimal amounts of drug substance while still performing a large number of experiments. High-throughput salt screening is used for both early phase salt selection studies and broad patent protection.

Salt selection – A powerful strategy for crystal form optimization

Pharmaceutical developers have focused efforts on finding and formulating a thermodynamically stable crystalline form with acceptable physical properties for a given compound. This is reasonable, given the need to avoid cascading from a meta-stable form to a more stable one in unpredictable fashion.

Occasionally certain physical properties, such as low aqueous solubility, are limiting to performance of the compound, leading to poor oral bioavailability or insufficient solubility for an injection formulation. One of the main strategies used to affect physical performance of a compound and one that is often employed by pharmaceutical scientists is the practice of salt selection (23). At least half of compounds in marketed products are in the form of a salt for one reason or another.

This fact alone speaks to the versatility of the salt selection approach. Salt forms of a pharmaceutical can have many benefits, such as improved stability characteristics, optimal bioavailability and aqueous solubility for an injectable formulation. Salts, like all other crystalline forms, are subject to polymorphism and solvate formation, thus requiring the same form identification studies as are needed for a neutral compound.

A remarkable example of co-optimization of properties is indinavir (HIV protease inhibitor), which is marketed as the sulfate salt ethanol solvate (24,25) The crystalline free base has variable oral bioavailability in dogs (26,27) and humans (28). While acidic solutions of the base compound showed good oral pharmacokinetics, the stability of the drug in acidic solution is not consistent with a product (26). Therefore, the discovery of the salt form ensured both shelf stability and robust bioavailability performance. The salt selection strategy is limited in two ways.

First, salt formation relies on the presence of one or more ionizable functional groups in the molecule; many drugs and development compounds lack this feature.

Second, our ability to predict a priori whether a given compound will form a crystalline salt (or salts) is non-existent. The ability to actively identify crystalline salt forms has been confined to manual empirical evaluation using multiple salt formers for a given acid or base. Recently advances have been made in the area of high-throughput salt selection and crystal engineering strategies associated with salt formation (14,29-32).

In one case, we have advocated the simultaneous assessment of polymorphism as a way to help rank the developability of different crystalline salts (14). While salt forms will continue to have a prominent place in pharmaceutical science, the need for enhanced productivity dictates that every advantage must be sought to aid the design of an appropriate crystalline form of an active molecule.

Specifically, the ability to design scaffolds into crystalline forms will enhance our capacity to convert interesting molecules into effective drugs. Crystal engineering offers some additional tools in this regard.

CASE STUDY FORM A ONLY US8084605

Figure imgf000073_0001TRELAGLIPTIN SUCCINATE

Form A may be prepared by crystallization from the various solvents and under the various crystallization conditions used during the polymorph screen (e.g., fast and slow evaporation, cooling of saturated solutions, slurries, and solvent/antisolvent additions). Tables B and C of Example 3 summarize the procedures by which Form A was prepared.

For example, Form A was obtained by room temperature slurry of an excess amount of Compound I in acetone, acetonitrile, dichloromethane, 1,4-dioxane, diethyl ether, hexane, methanol, isopropanol, water, ethylacetate, tetrahydrofuran, toluene, or other like solvents on a rotating wheel for approximately 5 or 7 days.

The solids were collected by vacuum filtration, and air dried in the hood. Also, Form A was precipitated from a methanol solution of Compound I by slow evaporation (SE). Form A was characterized by XRPD, TGA, hot stage microscopy, IR, Raman spectroscopy, solution 1H-NMR, and solid state 13C-NMR. Figure 1 shows a characteristic XRPD spectrum (CuKa, λ=1.5418A) of Form A. The XRPD pattern confirmed that Form A was crystalline. Major X-Ray diffraction lines expressed in °2Θ and their relative intensities are summarized in Table 1. Table 1. Characteristic XRPD Peaks (CuKa) of Form A

Figure imgf000018_0001 Figure imgf000019_0001

The above set of XRPD peak positions or a subset thereof can be used to identify Form A. One subset comprises peaks at about 11.31, 11.91, 12.86, 14.54, 15.81, 16.83, 17.59, 19.26, 19.52, 21.04, 22.32, 26.63, and 29.87 °2Θ. Another subset comprises peaks at about 11.31, 11.91, 19.26, 21.04, and 22.32 °2Θ; the peaks of this subset show no shoulder peaks or peak split greater than 0.2 °2Θ. Another subset comprises peaks at about 11.31, 11.91 and 22.32 °2Θ. Figure 2 is a TGA thermogram of Form A. TGA analysis showed that Form A exhibited insignificant weight loss when heated from 25 0C to 165 0C; this result is indicative that Form A was an anhydrous solid. Figure 3 shows a characteristic DSC thermogram of Form A. DSC analysis showed a single endothermic event occurred at approximately 195 0C (peak maximum). This endothermic event was confirmed by hot stage microscopy which showed the melting of Form A, which onset around 177 0C and the melting point estimated to be at approximately 184 0C.

Links

US8084605

Figure 4 (A-D) shows a characteristic FT-IR spectrum of Form A. The major bands expressed in reciprocal wavelengths (wavenumber in cm”1) are positioned at about 3815, 3736, 3675, 3460, 3402, 3141, 3098, 3068, 3049, 2953, 2934, 2854, 2760, 2625, 2536, 2481, 2266, 2225, 2176, 1990, 1890, 1699, 1657, 1638, 1626, 1609, 1586, 1553, 1517, 1492, 1478, 1450, 1419, 1409, 1380, 1351, 1327, 1289, 1271, 1236, 1206, 1180, 1158, 1115, 1087, 1085, 1064, 1037, 1027, 971, 960, 951, 926, 902, 886, 870, 831, 820, 806, 780, 760, 740, 728, 701, 685, 668, 637, 608, 594, 567, 558, and 516 cm”1 (values rounded to the nearest whole number). This unique set of IR absorption bands or a subset thereof can be used to identify Form A.

One such subset comprises absorption bands at about 3141, 3098, 3068, 3049, 2953, 2934, 2854, 2266, 2225, 1699, 1657, 1609, 1586, 1553, 1517, 1492, 1478, 1450, 1380, 1351, 1327, 1236, 1206, 1115, 1063, 902, 886, 870, 820, 780, 760, 685, 608, 594, and 516 cm 1. Another subset comprises absorption bands at about 3141, 2953, 2934, 2854, 2266, 2225, 1699, 1657, 1450, 1206, 886, 760, 685, 594, and 516 cm 1. Yet another subset comprises absorption bands at about 3141, 2953, 2934, 2266, 1699, 1657, 1450, and 1206 cm 1.

Links

Aprepitant case study FTIR.. READING MATERIAL http://alpha.chem.umb.edu/chemistry/ch361/spring%2005/ftir%20polymorph.pdf

Figure 5 (A-D) shows a characteristic Raman spectrum of Form A. The major Raman bands expressed in reciprocal wavelengths (wavenumber in cm”1) are positioned at about 3100, 3068, 3049, 2977, 2954, 2935, 2875, 2855, 2787, 2263, 2225, 2174, 1698, 1659, 1626, 1607, 1586, 1492, 1478, 1451, 1439, 1409, 1400, 1382, 1351, 1328, 1290, 1281, 1271, 1237, 1223, 1213, 1180, 1155, 1134, 1115, 1084, 1063, 1035, 971, 952, 926901, 868, 805, 780, 759, 740, 727, 701, 686, 669, 609, 594, 566, 558, 516, 487, 479, 433, 418, 409, 294, 274, 241, 218, 191 and 138 cm”1 (values rounded to the nearest whole number). This unique set of Raman bands or a subset thereof may be used to identify Form A.

One such subset comprises Raman bands at about 2954, 2935, 2225, 1698, 1659, and 1607 cm”1. Another subset comprises Raman bands at about 3068, 2954, 2935, 2225, 1698, 1659, 1607, 1586, 1223, 1180, 901, 780, 759, 669, and 516 cm”1. Yet another subset comprises Raman bands at about 3100, 3068, 2225, 1698, 1659, 1607, 1586, 1351, 1237, 1223, 1180, 1155, 1134, 1115, 1063, 952, 926, 901, 868, 805, 780, 759, 740, 669, 609, and 516 cm”1.

Form A was further characterized by solution 1H NMR and solid-state 13carbon NMR. The spectra are reported in Figures 6 and 7, respectively. Chemical assignments were not performed; however, the spectra are consistent with the known chemical structure of Compound I. US8084605

Figure imgf000073_0001 Example 11. Characterization of Form A Material prepared by the procedure of Example 1 was designated as Form A. The material was characterized by XRPD, TGA, DSC, hot stage microscopy, FT-IR, FT- Raman, 1H NMR, and 13C NMR. The analyses were conducted according to the procedures outlined in Section B of Example 3.

The characteristic spectra and thermograms for Form A are reported in Figures 1-7. The characterization data are summarized in Table D. Table D. Characterization Data of Form A of Compound I US8084605

Figure imgf000064_0001

Amorphous solid dispersion screening

Using the amorphous form of a drug substance offers several advantages with respect to dissolution rate and solubility of the substance. However, reduced chemical stability, increased hygroscopicity and, most important, physical instability are the major drawbacks of using the amorphous phase in the final drug product. These drawbacks can be overcome by stabilizing the amorphous phase of the API in a polymer matrix, e.q. an amorphous solid dispersion. Amorphous phases dissolve more rapidly than crystalline forms, and can significantly increase bioavailability of poorly water soluble drugs substances. However, the use of amorphous materials requires confidence that crystallization will not occur during the product lifespan. For a material that has never been obtained in a crystalline form, focus should be put on attempting to crystallize it. Crystallics has extensive experience of obtaining crystalline phases from amorphous materials.

Dispersions of a drug substance onto a polymeric matrix has received increased attention in recent years. A successful dispersion results in an amorphous solid material and will show improved dissolution rates and higher apparent solubility characteristics, as well as, sufficient resistance to chemical degradation and should be physically stable e.q. sufficient high glass transition temperature avoiding crystallization of the API.

A variety of factors contribute to the formation of a suitable Amorphous Solid Dispersion (ASD), including the nature of the polymer, the drug polymer ratio, the impact of surfactants and the solvent used in the process. Crystallics has developed high-throughput solid dispersion screening technology in order to find the optimal combination of these factors.

Example 10. Preparation of Amorphous Form US8084605

A sample of Compound I (40 mg) was dissolved in 1000 μl of water. The solution was filtered through a 0.2 μm nylon filter into a clean vial then frozen in a dry ice/acetone bath. The vials were covered with a Kimwipe then placed on a lyophilizer overnight. The resulting solids yielded Amorphous Form. 8. Amorphous Form The Amorphous Form of Compound I was prepared by lyophilization of an aqueous solution of Compound I (Example 10). The residue material was characterized by XRPD and the resulting XRPD spectrum displayed in Figure 26. The XRPD spectrum shows a broad halo with no specific peaks present, which confirms that the material is amorphous. The material was further characterized by TGA, DSC, hot stage microscopy, and moisture sorption analysis.

TGA analysis (Figure 27) showed a 1.8% weight loss from 25 0C to 95 0C, which was likely due to loss of residual solvent.

DSC analysis (Figure 28) showed a slightly concave baseline up to an exotherm at 130 0C (recrystallization), followed by an endotherm at 194 0C, which results from the melting of Form A. Hot stage microscopy confirmed these recrystallization and melting events (micrographs not included). An approximate glass transition was observed (Figure29) at an onset temperature of 82 0

C. 

Moisture sorption/desorption data (Figure 30 and Example 25) showed a 1.0% weight loss on equilibration at 5% relative humidity. Approximately 8% of weight was gained up to 65% relative humidity. Approximately 7% of weight was lost at 75% relative humidity. This is likely due to the recrystallization of the amorphous material to a crystalline solid. A 4.4% weight gain was observed on sorption from 75% to 95% relative humidity. Approximately 4.7% weight was lost on desorption from 95% to 5% relative humidity.

The solid material remaining after the moisture sorption analysis was determined to be Form A by XRPD (Figure 31). Table H. Characterization Data of Amorphous Form US8084605

Figure imgf000068_0001

T=temperature, RH=relative humidity, MB = moisture sorption/desorption analysis Example 19: Relative Humidity Stressing Experiments

 Moisture Sorption/Desorption Study of Amorphous Form.
Mositure sorption and desorption study was conducted on a sample of Amorphous Form. The sample was prepared by lyophilolization of a solution of Compound I in water (Example 3, section A.9). The mositure sorption and desorption study was conducted according to the procedures outlined in Example 3, section B.10. The data collected is plotted in Figure 29 and summarized in Table N .Table N. Moisture Sorption/Desorption of Amorphous Form
Figure imgf000072_0001

Table B. Crystallization Experiments of Compound I from Solvents

Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001

a) FE = fast evaporation; SE = slow evaporation; RT = room temperature; SC = slow cool; CC = crash cool, MB = moisture sorption/desorption analysis b) qty = quantity; PO = preferred orientation Table C. Crystallization Experiments of Compound I in Various Solvent/Antisolvent

Figure imgf000062_0002

a precipitated by evaporation of solvent Table A. Approximate Solubilities of Compound I US8084605

Figure imgf000052_0001
Figure imgf000053_0001

a) Approximate solubilities are calculated based on the total solvent used to give a solution; actual solubilities may be greater because of the volume of the solvent portions utilized or a slow rate of dissolution. Solubilities are reported to the nearest mg/mL.

Example 3.

Polymorph Screen Compound I as prepared by the method described in Example 1 was used as the starting material for the polymorph screen. Solvents and other reagents were of ACS or HPLC grade and were used as received. A. Sample Generation. Solids for form identification were prepared via the following methods from Compound I.

1. Fast Evaporation (FE) A solution of Compound I was prepared in test solvents. The sample was placed in the hood, uncovered, to evaporate under ambient conditions. The solids were analyzed by XRPD for form identification.

2. Slow Evaporation (SE) A solution of Compound I was prepared in test solvents. The sample was placed in the hood, covered with foil rendered with pinholes, to evaporate under ambient conditions. The solids were analyzed by XRPD for form identification.

3. Room Temperature (RT) Slurries An excess amount of Compound I was slurried in test solvent on a rotating wheel for approximately 5 or 7 days. The solids were typically collected by vacuum filtration, air dried in the hood, and analyzed by XRPD for form identification.

4. Elevated Temperature Slurries Excess Compound I was slurried in test solvents at 47 0C on a shaker block for approximately 5 days. The solids were collected by vacuum filtering, dried in the hood, and then analyzed by XRPD for form identification.

5. Slow Cooling Crystallization (SC)

A saturated or near saturated solution of Compound I was prepared at elevated temperature. The samples were filtered through warmed 0.2 μm filters into warmed vials. The heat source was turned off and the samples slowly cooled to ambient temperature. If precipitation did not occur within a day the samples were placed in the refrigerator. The samples were transferred to a freezer if precipitation did not occur within several days. The solids were collected by decanting the solvent or vacuum filtration, dried in the hood and analyzed by XRPD for form identification.

6. Crash Cooling Crystallization (CC) A saturated or near saturated solution of Compound I was prepared at elevated temperature. The samples were filtered through warmed 0.2 μm filters into warmed vials then rapidly cooled in an acetone/dry ice or ice bath. If precipitation did not occur after several minutes the samples were placed in the refrigerator or freezer. Solids were collected by decanting solvent or vacuum filtration, dried in the hood, and then analyzed by XRPD. Samples that did not precipitate under subambient conditions after several days were evaporated in the hood and analyzed by XRPD for form identification.

7. Solvent/Antisolvent Crystallization (S/AS) A solution of Compound I was prepared in test solvent. A miscible antisolvent was added with a disposable pipette. Precipitate was collected by vacuum filtration or decanting solvent. The samples were stored under subambient conditions if precipitation did not occur. If solids were not observed after several days the samples were evaporated in the hood. Collected solids were analyzed by XRPD for form identification.

8. Relative Humidity (RH) Stressing Experiments Samples of Compound I were placed uncovered in approximately 58%, 88%, and 97% relative humidity jars. The samples were stored in the jars for approximately 8 days. The solids were collected and analyzed by XRPD for form identification.

9. Lyophilization Compound I was dissolved in water in a glass vial. The solution was frozen by swirling the vial in an acetone/dry ice bath. The frozen sample was placed on the lyophilizer until all of the frozen solvent was removed. The solids were collected and analyzed by XRPD for form identification.

10. Grinding Experiments Aliquots of Compound I were ground manually with a mortar and pestle as a dry solid and a wet paste in water. The samples were ground for approximately three minutes. The solids were collected and analyzed by XRPD for form identification.

11. Dehydration Experiments Hydrated samples of Compound I were dehydrated at ambient conditions (2 days) and in an ambient temperature vacuum oven (1 day). The solids were collected and analyzed by XRPD for form identification.

12. Vapor Stress Experiments Amorphous Compound I was placed in acetone, ethanol, and water vapor chambers for up to eight days. The solids were collected and analyzed by XRPD for form identification.

STABILITY STUDY Stability studies are commonly performed for new drug entities with chemical stability and impurity formation being investigated. It is also important to monitor the physical stability under these same conditions to anticipate any form changes that may occur. As an example, many hydrates will dehydrate to a lower hydrate or anhydrous form at elevated temperatures. Anhydrous materials can also undergo form transformations to other anhydrous forms upon heating.

These types of changes can be monitored using heating studies in an oven with subsequent XRPD analysis or in-situ variable temperature XRPD can be used to look for changes. In other cases, anhydrates will convert to hydrates or the API in an amorphous solid dispersion may crystallize under elevated relative humidity (RH) conditions.

Equilibration in RH chambers with subsequent analysis by XRPD or in-situ variable RH XRPD experiments can be used to readily identify these form changes. Once the effect of temperature and RH on form changes is understood, this can be factored into other processes such as drying, formulation, storage, and packaging B. Sample Characterization. The following analytical techniques and combination thereof were used determine the physical properties of the solid phases prepared.

1. X-Ray Powder Diffraction (XRPD)

XRPD is commonly used as the initial method of analysis for form screens. For polymorph, salt, and co-crystal screens XRPD is used to determine if a new form has been produced by comparing the powder pattern to all known forms of the API and the counterion/guest. If a new form is found by XRPD, additional characterization by other methods is in order. For amorphous solid dispersion screens, XRPD is used to confirm a lack of crystallinity indicated by an amorphous halo in the powder pattern.

The halos will move depending on the concentration and interactions of the API and polymer. Computational methods have also been used with XRPD data to establish miscibility of amorphous solid dispersions X-ray powder diffraction is a front line technique in solid form screening and selection based on its ability to give a fingerprint of the solid-state structure of a pharmaceutical material. Understanding the solid forms of a pharmaceutical compound provides a road map to help direct a variety of development activities ranging from crystallization, formulation, packaging, storage, and performance.

Different screening and selection strategies are warranted in early and late development because different information is needed at the various stages. Solid form selection and formulation approaches need to be investigated together and tailored to the situation. It is important to include solid form selection and possible changes in form as part of the risk management strategy throughout the drug development process.

X-ray powder diffraction (XRPD) analyses were performed using an Inel XRG- 3000 diffractometer equipped with a CPS (Curved Position Sensitive) detector with a 2Θ (2Θ) range of 120°. Real time data were collected using Cu-Ka radiation starting at approximately 4 °2Θ at a resolution of 0.03 °2Θ. The tube voltage and amperage were set to 40 kV and 30 mA, respectively. The pattern is displayed from 2.5 to 40 °2Θ. Samples were prepared for analysis by packing them into thin- walled glass capillaries. Each capillary was mounted onto a goniometer head that is motorized to permit spinning of the capillary during data acquisition. The samples were analyzed for approximately 5 minutes.

Instrument calibration was performed using a silicon reference standard. Peak picking was performed using the automatic peak picking in the Shimadzu XRD-6000 Basic Process version 2.6. The files were converted to Shimadzu format before performing the peak picking analysis. Default parameters were used to select the peaks.

2. Thermogravimetric Analysis (TGA)

Thermogravimetric (TG) analyses were performed using a TA Instruments 2950 thermogravimetric analyzer. Each sample was placed in an aluminum sample pan and inserted into the TG furnace. The furnace was first equilibrated at 25 0C, then heated under nitrogen at a rate of 10 °C/min, up to a final temperature of 350 0C. Nickel and Alumel™ were used as the calibration standards.

3. Differential Scanning Calorimetry (DSC)

Differential scanning calorimetry (DSC) was performed using a TA Instruments differential scanning calorimeter 2920. The sample was placed into an aluminum DSC pan, and the weight accurately recorded. The pan was covered with a lid and then crimped. The sample cell was equilibrated at 25 0C and heated under a nitrogen purge at a rate of 10 °C/min, up to a final temperature of 350 0C. Indium metal was used as the calibration standard. Reported temperatures are at the transition maxima. For studies of the glass transition temperature (Tg) of the amorphous material, the sample cell was equilibrated at ambient temperature, then heated under nitrogen at a rate of 20 °C/min, up to 100 0C. The sample cell was then allowed to cool and equilibrate at -20 0C. It was again heated at a rate of 20 °C/min up to 100 0C and then cooled and equilibrated at -20 0C. The sample cell was then heated at 20 °C/min up to a final temperature of 350 0C. The Tg is reported from the onset point of the transition.

4. Hot Stage Microscopy.

Hot stage microscopy was performed using a Linkam hot stage (model FTIR 600) mounted on a Leica DM LP microscope. The samples were prepared between two cover glasses and observed using a 20χ objective with crossed polarizers and first order compensator. Each sample was visually observed as the stage was heated. Images were captured using a SPOT Insight™ color digital camera with SPOT Software v. 3.5.8. The hot stage was calibrated using USP melting point standards.

5. Thermogravimetric-Infrared (TG-IR)

Thermogravimetric infrared (TG-IR) analyses were acquired on a TA Instruments thermogravimetric (TG) analyzer model 2050 interfaced to a Magna 560® Fourier transform infrared (FT-IR) spectrophotometer (Thermo Nicolet) equipped with an Ever-Glo mid/far IR source, a potassium bromide (KBr) beamsplitter, and a deuterated triglycine sulfate (DTGS) detector. The TG instrument was operated under a flow of helium at 90 and 10 cc/min for the purge and balance, respectively. Each sample was placed in a platinum sample pan, inserted into the TG furnace, accurately weighed by the instrument, and the furnace was heated from ambient temperature to 250 0C at a rate of 20 °C/min.

The TG instrument was started first, immediately followed by the FT-IR instrument. Each IR spectrum represents 32 co-added scans collected at a spectral resolution of 4 cm“1. A background scan was collected before the beginning of the experiment. Wavelength calibration was performed using polystyrene. The TG calibration standards were nickel and Alumel™. Volatiles were identified from a search of the High Resolution Nicolet TGA Vapor Phase spectral library.

6. Fourier Transform Infrared Spectroscopy (FT-IR)

Infrared spectra were acquired on a Magna-IR 560® or 860® Fourier transform infrared (FT-IR) spectrophotometer (Thermo Nicolet) equipped with an Ever-Glo mid/far IR source, an extended range potassium bromide (KBr) beamsplitter, and a deuterated triglycine sulfate (DTGS) detector. A diffuse reflectance accessory (the Collector™, Thermo Spectra-Tech) was used for sampling. Each spectrum represents 256 co-added scans collected at a spectral resolution of 4 cm“1. Sample preparation consisted of physically mixing the sample with KBr and placing the sample into a 13 -mm diameter cup. A background data set was acquired on a sample of KBr. A Log 1/R (R = reflectance) spectrum was acquired by taking a ratio of these two data sets against each other. Wavelength calibration was performed using polystyrene. Automatic peak picking was performed using Omnic version 7.2.

7. Fourier Transform Raman Spectroscopy (FT-Raman)

FT-Raman spectra were acquired on a Raman accessory module interfaced to a Magna 860® Fourier transform infrared (FT-IR) spectrophotometer (Thermo Nicolet). This module uses an excitation wavelength of 1064 nm and an indium gallium arsenide (InGaAs) detector. Approximately 0.5 W of Nd)YVO4 laser power was used to irradiate the sample. The samples were prepared for analysis by placing the material in a glass tube and positioning the tube in a gold-coated tube holder in the accessory. A total of 256 sample scans were collected from at a spectral resolution of 4 cm“1, using Happ-Genzel apodization. Wavelength calibration was performed using sulfur and cyclohexane. Automatic peak picking was performed using Omnic version 7.2.

8. Solid State Nuclear Magnetic Resonance Spectroscopy (13C-NMR)

The solid-state 13C cross polarization magic angle spinning (CP/MAS) NMR spectrum was acquired at ambient temperature on a Varian UN1TYINOVA-400 spectrometer (Larmor frequencies: 13C = 100.542 MHz, 1H = 399.799 MHz). The sample was packed into a 4 mm PENCIL type zirconia rotor and rotated at 12 kHz at the magic angle. The spectrum was acquired with phase modulated (SPINAL-64) high power 1H decoupling during the acquisition time using a 1H pulse width of 2.2 μs (90°), a ramped amplitude cross polarization contact time of 5 ms, a 30 ms acquisition time, a 10 second delay between scans, a spectral width of 45 kHz with 2700 data points, and 100 co-added scans. The free induction decay (FID) was processed using Varian VNMR 6.1C software with 32768 points and an exponential line broadening factor of 10 Hz to improve the signal-to- noise ratio. The first three data points of the FID were back predicted using the VNMR linear prediction algorithm to produce a flat baseline. The chemical shifts of the spectral peaks were externally referenced to the carbonyl carbon resonance of glycine at 176.5 ppm. 9. Solution Nuclear Magnetic Resonance Spectroscopy (1H-NMR) The solution 1H NMR spectrum was acquired at ambient temperature with a

Figure imgf000058_0001

spectrometer at a 1H Larmor frequency of 399.803 MHz. The sample was dissolved in methanol. The spectrum was acquired with a 1H pulse width of 8.4 μs, a 2.50 second acquisition time, a 5 second delay between scans, a spectral width of 6400 Hz with 32000 data points, and 40 co-added scans. The free induction decay (FID) was processed using Varian VNMR 6.1C software with 65536 points and an exponential line broadening factor of 0.2 Hz to improve the signal-to-noise ratio. The spectrum was referenced to internal tetramethylsilane (TMS) at 0.0 ppm. 10.

Moisture Sorption/Desorption Analysis Moisture sorption/desorption data were collected on a VTI SGA-100 Vapor Sorption Analyzer. Sorption and desorption data were collected over a range of 5% to 95% relative humidity (RH) at 10% RH intervals under a nitrogen purge. Samples were not dried prior to analysis. Equilibrium criteria used for analysis were less than 0.0100% weight change in 5 minutes, with a maximum equilibration time of 3 hours if the weight criterion was not met. Data were not corrected for the initial moisture content of the samples. NaCl and PVP were used as calibration standards

Does solid form matter? 

Sometimes the properties of two solid forms of a drug are quite similar. In other cases, the physical and chemical properties can vary dramatically and have great impact on pharmacokinetics, ease of manufacturing, and dosage form stability. Properties that can differ among solid forms of a substance include color, solubility, crystal shape, water sorption and desorption properties, particle size, hardness, drying characteristics, flow and filterability, compressibility, and density.

Different solid forms can have different melting points, spectral properties, and thermodynamic stability. In a drug substance, these variations in properties can lead to differences in dissolution rate, oral absorption, bioavailability, levels of gastric irritation, toxicology results, and clinical trial results. Ultimately both safety and efficacy are impacted by properties that vary among different solid forms. Stability presents a special concern, since it’s easy to inadvertently generate the wrong form at any point in the development process.

Because energy differences between forms are usually relatively small, form interconversion is common and can occur during routine API manufacturing operations and during drug product formulation, storage, and use. The stakes are high. Encountering a new solid form during late stages of development can delay filing. A new form appearing in drug product can cause product withdrawal.  

When should a search for solid forms begin?

The key to speed in the drug development process is to do it right the first time. For solid pharmaceuticals, that means:

  • identify the optimum solid form early in drug development
  • make the same form for clinical material and commercial API
  • develop a crystallization process that assures control of solid form
  • produce a drug product with solid form stability through expiration

scientists strongly recommend that investigation of possible solid forms of a new chemical entity be carried out as early in the development process as drug supply will allow. The best approach has three stages. The first stage, more relevant to some development processes than to others, is a milligram-scale abbreviated screen on efficacious compounds prior to final IND candidate selection. This early information can be used to guide selection of salts and solid forms for scale-up and toxicology studies. The second stage is full polymorph screening and selection of optimum solid form. This stage is important to all development processes and should certainly occur before the first GMP material is produced. In the case of ionic drugs, various salts should be prepared and screened for polymorphs and hydrates. The third stage, an exhaustive screen carried out before drug launch, is an effort to find and patent all of the forms of a high-potential drug. Staging the screening in this way optimizes the balance among the factors of early knowledge of options, probability of commercial success, and judicious investment of R&D money.

Delay in understanding solid form issues results in problems like different batches of clinical material having different solid forms. Another common and preventable dilemma arises when clinical trials are carried out with one form while commercial production generates another. In this case, bridging studies are required to demonstrate to regulatory agencies that the clinicals are relevant. ICH guidelines require a search for solid forms, comparison of properties that might affect product efficacy, and, if appropriate, setting of solid form specifications.

How is solid form controlled in API manufacture? 

It is important to control solid form during API synthesis in order to demonstrate complete process control to regulatory agencies. Different solid forms can have different solubilities and can affect recovery of API. Purification efficiencies can vary due to differential exclusion of impurities. Filtration and transfer characteristics often differ between forms. Ease of drying can vary due to different abilities to bind solvent and water in the crystal lattice. A prevalent but incorrect belief is that solid form is determined primarily by choice of crystallization solvent. In fact, it is well established that parameters like temperature, supersaturation level, rate of concentration or cooling, seeding, and ripening can have an overriding effect. These variables must be controlled to ensure consistency of solid form in API.

Can solid form problems arise in drug products, too? 

The potential for solid form variation does not end at API production. Solid form issues remain through formulation, manufacture, storage, and use of drug product. It is common to observe form transformation during standard manufacturing operations like wet granulation and milling. Excipient interactions and compaction can induce form changes. Changes can occur in the final dosage form over time. Suspensions, including those in transdermal patches, are particularly vulnerable because they provide a low-energy pathway (dissolution/recrystallization) for form interconversion. Lyophile cakes are normally amorphous, but can crystallize on storage leading to difficulty in reconstitution. Even products containing drug in solution, such as filled gel caps, can be affected if the solution is or becomes supersaturated with respect to one of the possible solid forms of the drug.

How can you tell when you have a solid form problem? 

Whenever there is a specification failure in drug product or drug substance, solid form changes should be considered in the search for causes. Particularly symptomatic is failure to meet melting point or dissolution specifications. Changes in humidity, crystallization conditions, or crystallization solvent can produce unwanted forms. Solvents known to readily produce solvates include water, alcohols, chlorinated hydrocarbons, cyclic ethers, ketones, nitriles, and amides. Changes in the appearance of gel caps or cracking of tablet coatings can indicate solid form problems. Various solid-state analytical techniques can be used to identify solid form in API. Some techniques can even determine solid form of API in intact final dosage form. Among the most useful techniques for solid-state characterization are melting point, DSC, TGA, hot stage and optical microscopy, solid-state NMR, IR and Raman spectroscopy, and X-ray powder diffraction.

Is there any good news about polymorphism? 

Polymorphism presents opportunities as well as challenges. Investigation of the properties of different forms of a commercial drug can lead to new products with improved onset time, greater bioavailability, sustained release properties, or other therapeutic enhancements. New forms can bring improvements in manufacturing costs or API purity. These improvements are patentable and can provide a competitive advantage. An underutilized potential of polymorphism is to solve formulation problems that cause the abandonment of potentially useful drugs in which much investment has already been made.

SOLUBILITY

Solubility is an important parameter for new molecules especially with the emergence of many poorly soluble compounds in the drug discovery and development pipeline. Polymorphic forms can exhibit solubility differences that vary within a factor of 1-5, amorphous solid dispersions show an improvement one or two orders of magnitude higher, and salts and co-crystals fall between these extremes . A comparison of solubility values of pure forms will provide important information when deciding on a solid form or dosage form. X-ray powder diffraction will allow identification of pure forms for these types of measurements.

However, form changes during solubility and dissolution experiments are also possible and need to be investigated. Solids remaining at the end of solubility and dissolution experiments should always be analyzed initially by XRPD to determine if a form transformation has occurred under these conditions. If a form change has occurred, XRPD patterns can be compared to known forms (polymorphs, hydrates, salts, free acid/base) in order to identify the solids remaining. If a pattern is obtained that does not correspond to known forms, complementary methods will be needed to determine properties such as hydration state or a change in stoichiometry as would be observed from breaking a salt and forming the free acid/base or the formation of salts in buffered solutions.

FORMULATION

Formulators are charged with the responsibility to formulate a product which is physically and chemically stable, manufacturable, and bioavailable. Most drugs exhibit structural polymorphism, and it is preferable to develop the most thermodynamically stable polymorph of the drug to assure reproducible bioavailability of the product over its shelf life under a variety of real-world storage conditions. There are occasional situations in which the development of a metastable crystalline or amorphous form is justified because a medical benefit is achieved. Such situations include those in which a faster dissolution rate or higher concentration are desired, in order to achieve rapid absorption and efficacy, or to achieve acceptable systemic exposure for a low-solubility drug.

Another such situation is one in which the drug remains amorphous despite extensive efforts to crystallize it. If there is no particular medical benefit, there is less justification for accepting the risks of intentional development of a metastable crystalline or amorphous form. Whether or not there is medical benefit, the risks associated with development of a metastable form must be mitigated by laboratory work which provides assurance that (a) the largest possible form change will have no substantive effect on product quality or bioavailability, and/or (b) a change will not occur under all reasonable real-world storage conditions, and/or (c) analytical methodology and sampling procedures are in place which assure that a problem will be detected before dosage forms which have compromised quality or bioavailability can reach patients.

Crystal engineering and co-crystals

Crystal engineering is generally considered to be the design and growth of crystalline molecular solids with the aim of impacting material properties. A principal tool is the hydrogen bond, which is responsible for the majority of directed intermolecular interactions in molecular solids. Co-crystals are multi-component crystals based on hydrogen bonding interactions without the transfer of hydrogen ions to form salts – this is an important feature, since Brønsted acid-base chemistry is not a requirement for the formation of a co-crystal.

Co-crystallization is a manifestation of directed self-assembly of different components. Co-crystals have been described of various organic substances over the years (33,34) and given various names, such as addition compounds (35,36) molecular complexes (37,38) and heteromolecular co-crystals (39). Regardless of naming convention, the essential meaning is that of a multi-component crystal where no covalent chemical modification of the constituents occurs as a result of the crystal formation. Pharmaceuticals co-crystals have only recently been discussed as useful materials for drug products.  

Pharmaceutical co-crystals

Pharmaceutical co-crystals can be defined as crystalline materials comprised of an active pharmaceutical ingredient (API) and one or more unique co-crystal formers, which are solids at room temperature. Co-crystals can be constructed through several types of interaction, including hydrogen bonding, p-stacking, and van der Waals forces. Solvates and hydrates of the API are not considered to be co-crystals by this definition. However, co-crystals may include one or more solvent/water molecules in the crystal lattice. An example of putative design, a construction and preparation process is shown in Figure 2 for the 5-fluororuracil:urea 1:1 co-crystal(40).

This real example neatly illustrates the opportunity and challenge that exists currently with designing pharmaceutical co-crystals. Firstly, the ‘design’ is challenging because we have no ability to predict the exact crystal structure that may result from a crystallization attempt. By analogy to the challenge of deriving protein structure from first principles, the primary sequence (chemical structure in our case) is known and elements of secondary structure (the 2-D tape construction in Figure 2) are somewhat discernible from primary information. Prediction of the actual 3-D folded conformation (tertiary structure or obtained by self-assembly) is not possible. In other words, while we currently have the ability to project which things associate in what approximate manner on the secondary level, crystal structure prediction is essentially an intractable proposition.

By extension, and just as the exact function of a protein and quantitative parameters of activity are not predictable from primary and secondary structure, the prediction of crystal properties is not possible in the absence of structural information and measurements. There is early evidence that practitioners were aware that apparent co-crystallization of drugs could lead to useful preparations (41). In fact, a ‘chemical compound’ composed of sulfathiazole and proflavin dubbed flavazole was used to treat bacterial infection during the Second World War (42).

The case of flavazole reveals insight into how two different molecules might interact in a putative co-crystal:“… flavazole is definitely a chemical compound containing equimolar proportions of sulphathiazole and proflavin base. It is believed that combination occurs through the acidic sulphonamide group (SO2NH) of the sulphathiazole and the basic centres of the proflavin. Perhaps the most realistic expression of the formula would be to place proflavin and sulphathiazole side by side with a comma between them.” (42)  In the second half of the 20th century, interest in co-crystals evolved into the directed study of intermolecular interactions in crystalline solids (43-45). The technical development of routine single-crystal structure determination led to a watershed of data, now largely accessible through the Cambridge Structural Database (CSD) (46,47).

The structural data have become useful for understanding the intermolecular interactions in co-crystals in atomic level detail (48). Using insight gained from analysis of the CSD and directed experimentation, scientists attempt design of co-crystals with specific properties, such as color or non-linear optical response, by selecting starting components with appropriate molecular properties likely to exhibit specific intermolecular interactions in a crystal (49-52).

However, even when chemically compatible functional groups are present it is not possible to accurately predict if a co-crystal, a eutectic mixture or simply a physical mixture will result from any given experiment. As a result of these complexities, attention has been directed at the identification and characterization of intermolecular packing motifs with the goal of developing principles for co-crystal materials (53).

Figure 2.  Steps involved in crystal engineering of a pharmaceutical phase, exemplified by the real example of co-crystallization of 5-fluorouracil and urea. Scientists in India have reported a rare example of synthon polymorphism in co-crystals of 4,4′-bipyridine and 4-hydroxybenzoic acid.

Graphical abstract: Synthon polymorphism and pseudopolymorphism in co-crystals. The 4,4′-bipyridine–4-hydroxybenzoic acid structural landscape

Polymorphism is defined as the ability of a material to exist in more than one form or crystal structure. It has important implications for the properties of such materials; for example in pharmaceuticals, the dissolution rate of a drug can be dependent on the polymorphic form. While this is a common phenomenon in single crystals it is much less common in co-crystals, systems where the structure has at least two distinct components. Gautam Desiraju from the Indian Institute of Science, found that when 4,4′-bipyridine and 4-hydroxybenzoic acid were dissolved together in a solvent such as methanol they would co-crystallise to form two different polymorphs. They noticed that a third form, a pseudopolymorph, was also present.

PROSPECTS FOR CRYSTAL ENGINEERING AND PHARMACEUTICAL CO-CRYSTALS

At the beginning of the 21st century, the field of crystal engineering has experienced significant development. Importantly, crystal engineering principles are now being actively considered for application to pharmaceuticals to modulate the properties of these valuable materials (54).

Because the physical properties that influence the performance of pharmaceutical solids are reasonably well appreciated, there is a unique opportunity to apply crystal engineering techniques and the appropriate follow-up studies to solve real world problems, such as poor physical and chemical stability or inadequate dissolution for appropriate biopharmaceutical performance of an oral drug. As structures and series of pharmaceutical co-crystals have begun to appear, we again find that properties cannot be predicted from the structures.  Nevertheless, occasional trends have been suggested.

For example, insoluble drug compounds co-crystallized with highly water soluble complements tend to achieve kinetic solubilities in aqueous media several times greater than the pure form (55,56).

There are also more possible phases for each given active compound to consider, thus there will arguably be a greater opportunities for property enhancement. In terms of stability enhancement and solubilization, the example of the series of itraconazole co-crystals with pharmaceutically acceptable 1,4-diacids (55) suggests a strategy alternative to amorphous drug formulation. The co-crystal options presented retain the stability inherent in a crystalline state, while allowing for solubilization that significantly exceeds that of crystalline itraconazole base and rivals the performance of the engineered amorphous bead formulation (Sporanox®).

Where are we now? From recent literature it appears that knowledge gained over the past century and increasingly sophisticated screening techniques developed within the last decade are paving the way towards design of co-crystals with potentially improved pharmaceutical properties (55-58) In terms of the application to pharmaceutical systems, the field of crystal engineering is developing the retro-synthetic understanding of crystal structure using reasoning that is analogous to that applied by organic chemists.  For example, the retro-synthetic approach in covalent synthesis operates on the level of a single molecule, while the analogous effort in crystal engineering focuses on the “supermolecule”:

piracetam

The assemblies that define the crystalline arrangement of the molecules as they self-organize into the solid-state. The parallels between the development of crystal engineering and synthetic organic chemistry run still deeper. Methodologies for carrying out these crystallizations are being developed alongside the development of new robust motifs (6,53,55,57,60). The importance of the solubility and dissolution relationships of the components of a putative co-crystal is becoming a matter of significant investigation (56,60). The same can be said for the roles of additives in templating novel forms.

Mechanical milling of materials has also been documented as a means to make co-crystals, and a recent example of polymorphic forms of caffeine:glutaric acid illustrates the opportunities of this type of processing to influence crystal form (61). With an increase in the understanding of the modes of self-assembly, one can start to address the design aspect towards making pharmaceutical co-crystals.

There remain several limitations to the application of what is currently known to the design of useful materials. As mentioned earlier, it remains intractable to reliably predict crystal structure.  Multi-component crystals are well out of reach for prediction due in part to complex energetic landscapes, lack of appropriate charge density models and a large number of degrees of freedom, making computation unfeasible. Moreover, there is only a qualitative understanding of the interplay between intermolecular interactions and materials performance, especially for properties relevant to pharmaceuticals such as solubility, dissolution profile, hygroscopicity and melting point.

But the saving grace of the co-crystal approach comes in two guises: Complementarity and diversity. On the topic of complementarity, it is possible, by way of CSD database mining for instance, to identify trends of hetero-synthon occurrence in model systems. As for the diversity aspect, the space of possible co-crystal formers is large, limited only by pharmaceutical acceptability. Coupled with parameters such as stoichiometry variation and increase in the number of components (binary systems can be expanded into ternary ones, etc.), the opportunities appear vast.

THE FUTURE OF CRYSTAL ENGINEERING IN PHARMACEUTICAL SCIENCE

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Novel Challenges in Crystal Engineering: Polymorphs and New 

http://www.intechopen.com/…/novel-challenges-in-crystal-engineering-polymNovel Challenges in Crystal Engineering: Polymorphs and New Crystal Forms of ActivePharmaceutical Ingredients

Where are we going?  At this point, we have only just scratched the surface of materials science-driven pharmaceutical product design. In the 21st century, practitioners of pharmaceutical chemistry need to enumerate and exploit the opportunities of crystal form design that nature affords us, and thus gain increasing ability to design the materials we need from the molecules that we seek to convert into pharmaceuticals.

Learning will be facilitated by advances in crystallization automation (6,62), microscopy-spectroscopy techniques (Raman and IR microscopy) and new techniques such as terahertz spectroscopy and AFM, along with increasingly sophisticated X-ray diffraction lab instrumentation. In addition, further enhancements in the data mining tools associated with the CSD operating on an ever increasing number of high-quality crystal structures will undoubtedly lead to new knowledge and principles of interaction.

The challenge placed before pharmaceutical scientists, now and in the future, is the following: (i) to understand the requirement of a particular compound in terms of materials structure and properties, and (ii) to creatively integrate crystal engineering within the limits of pharmaceutical acceptability of components to obtain new forms of active ingredients with desirable properties for formulation and delivery. It should become the collective mantra of medicinal chemists, process engineers and pharmaceutical scientists to “design and make the material we need.” This mantra can form the common aspiration for an industry that is in significant need of innovation and productivity enhancement.

Applications and Advantages

Applications

  • Drug companies can use this technology to protect themselves against others generating and patenting polymorphs

Advantages

  • Having more than one solid form of a drug allows optimization of drug dissolution behavior and shelf life

IP AND POLYMORPHS

In order for a new drug to enter the market, pharmaceutical companies must invest for many years in very expensive clinical trials and a lengthy regulatory approval process.Market protection plays therefore a major role in the growth of the pharmaceutical industry and Intellectual Property (IP) laws are intended to give the investors an opportunity to recover their costs. Patent filing is one way of efficiently protecting various aspects of an innovative drug.
The duration of the new drug’s market protection is, however, limited in time and once the original drug is no longer protected, legal copies (generic medicines) can be developed and marketed by competitors at more accessible prices, since the expensive basic research, as well as pre-clinical and clinical trials (at least for small molecules) are no longer necessary. Generic medicines are either identical copies of the original drug or so-called bioequivalent versions of it.
Bioequivalent means that they behave as the original drug when administered to patients. For a generic drug to be a bioequivalent its Active Pharmaceutical Ingredient (API) does not need to be the same solid form as in the original drug. A different polymorph or a pseudo-polymorph (i.e. solvate, hydrate) of the API and different excipients are acceptable variants, as long as the final generic drug product behaves as the original one.  
Solid Forms Screening
Screening of solid forms, in particular polymorphs of APIs, is therefore an essential part of pharmaceutical development and lifecycle management, not only for scientific and regulatory reasons, but also because of the key role that pharmaceutical solid forms play in the area of IP, for innovators as well as for generic companies. The knowledge generated by conducting solid form screening, in fact, can provide an innovator company the opportunity to build a strong patent portfolio around different solid forms and therefore a way to maximize returns from drug development.
This allows innovator companies to gain several years of additional protection for their product after the expiry of the basic molecule patent, since various pharmaceutical solid forms are individually patentable. In the US, for instance, innovator companies are required to identify, in the so-calledOrange Book, their patents covering different solid forms performing the same as the product described in the corresponding NDA. In return, they can benefit from a 30-months stay over a generic company which would eventually file an ANDA with aParagraph IV Certification for any of these listed patents.
 
Thus, by patenting a maximum number of possible solid forms, even if these are not further developed and used, innovator companies can more efficiently protect their own products. Such patents must obviously meet the same patentability criteria as other inventions. Conversely, a generic company can launch its own product if, after the basic molecule patent has expired, it discovers a new solid form, i.e. a form with no IP protection and suitable characteristics for product development.
In both cases, a very sensitive tool as SR-XRPD can play a key role in helping the detection and characterization of a maximum number of polymorphs.
 Accurate and direct characterization of the API polymorphic forms and detection of trace amounts has proven to be of paramount importance (e.g. Paxil®, Cefdinir) whereas poorly conducted screens and unsuccessful patenting strategies, on the other hand, can have significant negative commercial consequences (e.g. Ritonavir).
Interestingly, in the US the first ANDA approved by FDA with paragraph IV certification is entitled to 180-days marketing exclusivity. Initially granted only when theANDA applicant having filed Paragraph IV Certification could prevail in the litigation with the originator, the new FDA guidance suppresses the “successul defence”requirement and the 180-days exclusivity is decided on a case-by-case basis and can therefore be granted even if the case is settled.
While there has been much discussion by policymakers and stakeholders about the effects of “secondary patents” on the pharmaceutical industry, there is no empirical evidence on their prevalence or determinants. Characterizing the landscape of secondary patents is important in light of recent court decisions in the U.S. that may make them more difficult to obtain, and for developing countries considering restrictions on secondary patents.
It is seen the claims of the 1304 Orange Book listed patents on all new molecular entities approved in the U.S. between 1988 and 2005, and coded the patents as including chemical compound claims (claims covering the active molecule itself) and/or one of several types of secondary claims. It is seen that  distinguish between patents with any secondary claims, and those with only secondary claims and no chemical compound claims (“independent” secondary patents).
It is seen  that secondary claims are common in the pharmaceutical industry. It is seen that independent secondary patents tend to be filed and issued later than chemical compound patents, and are also more likely to be filed after the drug is approved. When present, independent formulation patents add an average of 6.5 years of patent life (95% C.I.: 5.9 to 7.3 years), independent method of use patents add 7.4 years (95% C.I.: 6.4 to 8.4 years), and independent patents on polymorphs, isomers, prodrug, ester, and/or salt claims add 6.3 years (95% C.I.: 5.3 to 7.3 years). evidence that late-filed independent secondary patents are more common for higher sales drugs
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Polymorph quantification. REF 79
SEE A SLIDESHARE PRESENTATION
The ability to detect and quantify polymorphism of pharmaceuticals is critically important in ensuring that the formulated product delivers the desired therapeutic properties because different polymorphic forms of a drug exhibit different solubilities, stabilities and bioavailabilities. The purpose of this study is to develop an effective method for quantitative analysis of a small amount of one polymorph within a binary polymorphic mixture. Sulfamerazine (SMZ), an antibacterial drug, was chosen as the model compound. The effectiveness and accuracy of powder X-ray diffraction (PXRD), Raman microscopy and differential scanning calorimetry (DSC) for the quantification of SMZ polymorphs were studied and compared.
Low heating rate in DSC allowed complete transformation from Form I to Form II to take place, resulting in a highly linear calibration curve. Our results showed that DSC and PXRD are capable in providing accurate measurement of polymorphic content in the SMZ binary mixtures while Raman is the least accurate technique for the system studied.
DSC provides a rapid and accurate method for offline quantification of SMZ polymorphs, and PXRD provides a non-destructive, non-contact analysis.A novel method of detecting very low levels of different polymorphs using high-resolution X-ray powder diffraction with a synchrotron light source has been developed by Zach-Zambon Chemicals of Italy. Key to the project has been development of software to enable appropriate data presentation.The issue of polymorphism in pharmaceuticals has attracted increasing attention over the past 20 years and is something to which development scientists and the regulatory authorities pay considerable attention.
Links

REFERENCES

Links

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63……..POLYMORPHISM AND PATENTS http://www.collegio.unibo.it/uploads/ideas/joelbernstein.pdf 64…Aprepitant case study FTIR.. READING MATERIALhttp://alpha.chem.umb.edu/chemistry/ch361/spring%2005/ftir%20polymorph.pdf 65…..READ………….An Overview of Solid Form Screening During Drug Development, http://www.icdd.com/ppxrd/10/presentations/PPXRD-10_Ann_Newman.pdf 66…..CRYSTALLIZATION..http://www.intechopen.com/books/advanced-topics-on-crystal-growth/crystallization-from-the-conformer-to-the-crystal

67International Conference on Harmonization Q6A Guideline: Specifications for New Drug Substances and Products: Chemical Substances, October 1999.

68Center for Drug Evaluation and Research Guidance: Submitting Supporting Documentation in Drug Applications for the Manufacture of Drug Substances, February 1987.

69S. Byrn, R. Pfeiffer, M. Ganey, C. Hoiberg, and G. Poochikian. Pharmaceutical solids: A strategic approach to regulatory considerations. Pharm. Res. 12:945-954 (1995). 70

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71 CRYSTALS POLYMORPHS IN PHARMAhttp://www.fcfar.unesp.br/arquivos/475753.pdf

72 API………….POLYMORPHISM pharmaceutical ingredients (APIs).http://www.ncbi.nlm.nih.gov/pubmed/19275600

73 polymorphs and co-crystals – ICDD  POWER POINT PRESENTATION

74Thermodynamic stability and transformation of pharmaceutical  http://pac.iupac.org/publications/pac/pdf/2005/pdf/7703×0581.pdf

75http://www.imc.cas.cz/nmr/projekt/ws/springer.pdf

76  High-throughput crystallization: polymorphs, salts, co-crystalsand solvates of pharmaceutical solidshttp://citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.85.5397&rep=rep1&type=pdf

77 Crystalline Solid – University of Utah College of Pharmacy Homepharmacy.utah.edu/pharmaceutics/pdf/Crystalline.pdf‎Form – a term encompassing all solids – polymorphs, solvates, amorphous  inPolymorphism in Pharmaceutical Solids

Links

78..related to xrd

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  7. Bergamaschi, A.; Cervellino, A.; Dinapoli, R.; Gozzo, F.; Henrich, B.; Johnson, I.; Kraft, P.; Mozzanica, A.; Schmitt, B.; Shi, X.: The MYTHEN detector for X-ray powder diffraction experiments at the Swiss Light Source. J. Synchrotron Rad. 17 (2010) 653–668.
  8. R.B. Von Dreele, P.W. Stephens, G.D. Smith, and R.H. Blessing: The First Protein Crystal Structure Determined from X-ray Powder Diffraction Data: a Variant of T3R3 Human Insulin Zinc Complex Produced by Grinding,Acta Cryst. D 56, 1549-53 (2000).
  9. Margiolaki, I., Wright, J. P., Fitch, A. N., Fox, G. C. & Von Dreele, R. B.: Synchrotron X-ray powder diffraction study of hexagonal turkey egg-white lysozyme, Acta Cryst. D61, 423–432 (2005). See also: Margiolaki, I. & Wright, J. P.: Powder crystallography on macromolecules, Acta Cryst. A64, 169–180 (2008).
  10. Fundamentals of Crystallography,C. Giacovazzo Ed., International Union of Crystallography, Oxford Science Publications, Third Edition (2011).
  11. The basics of Crystallography and Diffraction (Third edition, 2010), Christopher Hammond, IUCr, Oxford Science Publications; ISBN 978-0-19-954645-9. See also: X-Ray Structure Determination, A practical Guide, George H. Stout and Lyle H. Jensen, Wiley Interscience.
  12. Bruni G, Gozzo F, Capsoni D, Bini M, Macchi P, Simoncic P, Berbenni V., Milanese C., Girella A., Ferrari S. and Marini A., Thermal, Spectroscopic, and Ab Initio Structural Characterization of Carprofen Polymorphs, J. Pharm. Sciences 100(6), 2321 (2011).
  13. Brunelli, M., Wright, J. P., Vaughan, G. B. M., Mora, A. J. & Fitch, A. N.: Solving Larger Molecular Crystal Structures from Powder Diffraction Data by Exploiting Anisotropic Thermal Expansion. Angew. Chem. (2003) 115, 2075–2078.
  14. T. Wessels, Ch. Baerlocher and L.B. McCusker: Single-crystal-like diffraction data from polycrystalline materials, Science (1999), 284, 477-479.
  15. Shankland, K., David, W. I. F., Csoka, T. & McBride, L.: Structure solution of Ibuprofen from powder diffraction data by the application of a genetic algorithm combined with prior conformational analysis,  Intl. J. Pharmaceut. (1998) 165, 117–126.
  16. A. Altomare, C. Cuocci, C. Giacovazzo, A. Moliterni and R. Rizzi: The dual-space resolution bias correction algorithm: applications to powder data, J. Appl. Cryst. (2010). 43, 798-804.
  17. G.Oszlanyi and A. Suto: The charge flipping algorithm, Acta Cryst. (2008). A64, 123–134 and references herein.
  18. Boccaleri, E., Carniato, F., Croce, G., Viterbo, D., van Beek, W., Emerich H. and Milanesio, M.,In-situ simultaneous Raman/high-resolution X-ray powder diffraction study of transformations occurring in materials at non-ambient conditions, J. Appl. Cryst., 2007, 40, 684-693.
  19. Scarlett N.V.Y. and Madsen I. C., Quantification of phases with partial or no known crystal structures, Powder Diffraction (2006) 21, 278-284
  20. Giannini C., Guagliardi A. and Millini R., Quantitative phase analysis by combining the Rietveld and the whole-pattern decomposition methods, J. Appl. Cryst., 2002, 35, 481-490.
  21. Scardi, P.; Leoni, M.: Line profile analysis: pattern modeling versus profile fitting, J. Appl. Cryst. 39 (2006) 24–31. Scardi, P.; Leoni, M.: Whole Powder Pattern Modelling, Acta Crystall. A58 (2002) 190–200
  22. Local structure from total scattering and atomic pair distribution function (PDF) analysis, In Powder diffraction: theory and practice, (Royal Society of Chemistry, London England, 2008), Robert E. Dinnebier and Simon J. L. Billinge, Eds., pp. 464 – 493.
  23. Neder R. B. And Korsunskiy V. I., Structure of nanoparticles from powder diffraction data using the pair distribution function, 2005 J. Phys.: Condens. Matter 17 S125
  24. A. Cervellino, C. Giannini, A. Guagliardi, Determination of nanoparticle, size distribution and lattice parameter from x-ray data for monoatomic materials with f.c.c. cubic unit cell, J. Appl. Cryst. 36, 1148-1158 (2003).
  25. P.W. Stephens, D.E. Cox, and A.N. Fitch, Synchrotron Radiation Powder Diffraction in Structure Determination by Powder Diffraction, pp. 49-87, edited by W.I.F. David, K. Shankland, L.B. McCusker, and C. Baerlocher, (Oxford University Press, 2002)
  26. Joel Bernstein: Polymorphism in Molecular Crystals, IUCr Monographs on Crystallography (2002), Oxford Science Publications.
  27. Polymorphism in Pharmaceutical Solids, Ed. By Harry G. Brittain, Drugs and The Pharmaceutical Sciences, Vol. 192
  28. Tremayne, M.: The impact of powder diffraction on the structural study of organic materials., Philosophical Transactions of the Royal Society of London Series A: Chemistry and Life Sciences Triennial Issue, 362: 2691 (2004).
  29. Law D, Schmitt EA, Marsh KC, Everitt EA,Wang W, Fort JJ, Krill SL, Qiu Y. Ritonavir-PEG 8000 amorphous solid dispersions: in vitro and in vivo evaluations. J. Pharm. Sci. 2004; 93 (3): 563–567.
  30. Bruni G., Berbenni V., Milanese C., Girella A., Cardini A., Lanfranconi S. and Marini A.,Determination of the nateglinide polymorphic purity through DSC, J. Pharm. and Biomed. Anal. 54 (2011) 1196-1199.
  31. Aaltonen J., Alleso M., Mirza S., Koradia V., Gordon K.C and Rantanen J., Solid form screening – A review. European Journal of Pharmaceutics and Biopharmaceutics 71 (2009), 23-37.
  32. Srivastava D., The Food and Drug Administration and Patent Law at a Crossroads: The Listing of Polymorph Patents as a Barrier to Generic Drug Entry. Food and Drug Law Journal, Vol. 59, No.2 (2004), 339-354.
  33. Grabowski H. G., Kyle M., Mortimer R., Long G. & Kirson N., Evolving Brand-name And Generic Drug Competition May Warrant A Revision Of The Hatch-Waxman Act. Health Affairs, 30, no.11 (2011):2157-2166.
  34. Rakowski W. A and Mazzochi D. M., The case of disappearing polymorph: ‘Inherent anticipation’ and the impact of Smithkline Beecham Corp. v Apotex Corp. (Paxil®) on patent validity and infringement by inevitable conversion’. Journal of Generic Medicine, Vol.1, No.2 (2006):131-139.
  35. Cabri W., Ghetti P., Pozzi G. and Alpegiani M., Polymorphisms and Patent, Market, and Legal Battles: Cefdinir Case Study. Organic Process Research & Development 2007, 11, 64-72.
  36. Bauer J, Spanton S, Henry R, Quick J, Dziki W, Porter W, Morris J., Ritonavir: an extraordinary example of conformational polymorphism, Pharm Res. 2001 Jun;18(6):859-66.

Links

79………..related to estimation

  1. McCrone, W.C. in Physics and Chemistry of the Organic Solid State, Vol. 2, (Eds.: D. Fox, M.M. Labes, A. Weissberger), Interscience, New York, 1965, pp. 725-767.
  2. Bernstein, J., Davey, R.L., and Henck, JO, Concomitant Polymorphism, Angew.Chem.Int. Ed. 1999,38, 3440-3461.
  3. Polymorphism in Pharmaceutical Solids, Second Edition (Drugs and the Pharmaceutical Sciences) Harry G. Brittain (Editor) Informa HealthCare; 2nd edition (July 27, 2009)
  4. Otsuka, M., Kato, F. and Matsuda, Y., Determination of indomethacin polymorphic contents by chemometric near-infrared spectroscopy and conventional powder X-ray diffractometry, Analyst, 2001, 126, 1578 – 1582.
  5. Patel, A.D., Luner, P. E. and Kemper, M. S., Low-level Determination of Polymorph composition in Physical Mixtures by Near-Infrared Reflectance Spectroscopy, J Pharm Sci 2001, 90, 360-370.
  6. Agatonovic-Kustrin S, Wu V, Rades, T, Saville, D, Tucker, I G, Powder diffractometric assay of two polymorphic forms of ranitidine hydrochloride Int J Pharm 1999, 184, 107.
  7. Hurst, V.J., Schroeder, P.A., and Styron, R.W. Accurate quantification of quartz and other phases by powder X-ray diffractometry. Analytica Chimica. Acta, 1997, 337, 233-252
  8. Campbell Roberts, S.N., Williams A.C., Grimsey, I.M., and Booth S.W., Quantitative analysis of mannitol polymorphs. X-ray powder diffractometry—exploring preferred orientation effects J. Pharm. Biomed. Anal., 2002, 28, 1149-1159.

SEE

PART 1………..http://drugsynthesisint.blogspot.in/p/gliptin-series.html

PART 2 ……http://organicsynthesisinternational.blogspot.in/p/gliptin-series-22.html

COCRYSTALS IN PHARMA


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http://www.allfordrugs.com/cocrystals/

Integrated Drug Discovery Technologies


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New Drug Shows Promise for Type 2 Diabetes


TUESDAY Sept. 3, 2013 — An injectable drug that mimics the action of a little-known hormone may hold promise for patients with type 2 diabetes.

The experimental drug, called LY, is a copy of a hormone called fibroblast growth factor 21 (FGF21), and researchers report that it seems to help protect against obesity and may boost the action of insulin.

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http://www.drugs.com/news/new-shows-promise-type-2-diabetes-47140.html

FGF21

Fibroblast growth factor 21 is a member of the fibroblast growth factor (FGF) family. FGF21 stimulates glucose uptake in adipocytes but not in other cell types.This effect is additive to the activity of insulin. FGF21 treatment of adipocytes is associated with phosphorylation of FRS2, a protein linking FGF receptors to the Ras/MAP kinase pathway.
FGF21 injection in ob/ob mice results in an increase in Glut1 in adipose tissue. FGF21 also protects animals from diet-induced obesity when overexpressed in transgenic mice and lowers blood glucose and triglyceride levels when administered to diabetic rodents. Treatment of animals with FGF21 results in increased energy expenditure, fat utilization and lipid excretion

http://alfin2600.blogspot.in/2012/10/fgf21-learning-to-live-longer-from.html

Fibroblast growth factor-21 (FGF21) is a hormone secreted by the liver during fasting that elicits diverse aspects of the adaptive starvation response. Among its effects, FGF21 induces hepatic fatty acid oxidation and ketogenesis, increases insulin sensitivity, blocks somatic growth and causes bone loss. Here we show that transgenic overexpression of FGF21 markedly extends lifespan in mice without reducing food intake or affecting markers of NAD+ metabolism or AMP kinase and mTOR signaling. Transcriptomic analysis suggests that FGF21 acts primarily by blunting the growth hormone/insulin-like growth factor-1 signaling pathway in liver. These findings raise the possibility that FGF21 can be used to extend lifespan in other species

 

Type II diabetes is the most prevalent form of diabetes. The disease is caused by insulin resistance and pancreatic β cell failure, which results in decreased glucose-stimulated insulin secretion. Fibroblast growth factor (FGF) 21, a member of the FGF family, has been identified as a metabolic regulator and is preferentially expressed in the liver and adipose tissue and exerts its biological activities through the cell surface receptor composed of FGFR1c and β-Klotho on target cells such as liver and adipose tissues (WO0136640, and WO0118172).

The receptor complex is thought to trigger cytoplasmic signaling and to up-regulate the GLUT1 expression through the Ras/MAP kinase pathway.

Its abilities to provide sustained glucose and lipid control, and improve insulin sensitivity and β-cell function, without causing any apparent adverse effects in preclinical settings, have made FGF21 an attractive therapeutic agent for type-2 diabetes and associated metabolic disorders.

There have been a number of efforts towards developing therapies based on FGF21. WO2006065582, WO2006028714, WO2006028595, and WO2005061712 relate to muteins of FGF21, comprising individual amino-acid substitutions. WO2006078463 is directed towards a method of treating cardiovascular disease using FGF21. WO2005072769 relates to methods of treating diabetes using combinations of FGF21 and thiazolidinedione. WO03059270 relates to methods of reducing the mortality of critically ill patients comprising administering FGF21. WO03011213 relates to a method of treating diabetes and obesity comprising administering FGF21.

However, many of these proposed therapies suffer from the problem that FGF21 has an in-vivo half-life of between 1.5 and 2 hrs in humans. Some attempts have been made to overcome this drawback. WO2005091944, WO2006050247 and WO2008121563 disclose FGF21 molecules linked to PEG via lysine or cysteine residues, glycosyl groups and non-natural amino acid residues, respectively. WO2005113606 describes FGF21 molecules recombinantly fused via their C-terminus to albumin and immunoglobulin molecules using polyglycine linkers.

However, developing protein conjugates into useful, cost-effective pharmaceuticals presents a number of significant and oftentimes competing challenges: a balance must be struck between in vivo efficacy, in vivo half-life, stability for in vitro storage, and ease and efficiency of manufacture, including conjugation efficiency and specificity. In general, it is an imperative that the conjugation process does not eliminate or significantly reduce the desired biological action of the protein in question.

The protein-protein interactions required for function may require multiple regions of the protein to act in concert, and perturbing any of these with the nearby presence of a conjugate may interfere with the active site(s), or cause sufficient alterations to the tertiary structure so as to reduce active-site function. Unless the conjugation is through the N′ or C′ terminus, internal mutations to facilitate the linkage may be required. These mutations can have unpredictable effects on protein structure and function. There therefore continues to be a need for alternative FGF21-based therapeutics.

The reference to any art in this specification is not, and should not be taken as, an acknowledgement of any form or suggestion that the referenced art forms part of the common general knowledge.

DRUG DISCOVERY PRESENTATION BY DR ANTHONY CRASTO


 

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Sponge molecules isolated and synthesized for drug trials


A structure of PM060184.

By scouring the oceans for disease-fighting molecules, researchers have identified two new anticancer compounds. Isolated from a sea sponge, the compounds represent a new class of the natural products called polyketides, many of which have biological activity. Because it’s not possible to extract sufficient amounts of the molecules from the sponges, the researchers also devised chemical syntheses that allowed them to make enough material to initiate clinical trials on one of the substances,

Cancer Fighters From The Sea

Natural Products: Sponge molecules isolated and synthesized for drug trials.

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http://cen.acs.org/articles/91/i25/Cancer-Fighters-Sea.html

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